CN101405001A - Methods of inhibiting BTK and SYK protein kinases - Google Patents

Abstract

Methods of inhibiting a tyrosine kinase wherein said tyrosine kinase is BTK or SYK comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula (I) as described in claim 1 are disclosed. The compounds are useful for treating auto-immune and inflammatory diseases.

Description

Methods of inhibiting BTK and SYK protein kinases

The present invention relates to the use of novel phthalazinone derivatives for the treatment of autoimmune and inflammatory diseases caused by abnormal B cell activation. The new phthalazinones are effective for the treatment of asthma, rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis.

Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins; in particular tyrosine kinases phosphorylate the alcohol moiety of proteins on tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration and differentiation. Aberrant kinase activity has been implicated in many human diseases, including cancer, autoimmune and inflammatory diseases. Since protein kinases are among the key regulators of cellular signaling, they provide a means to modulate cellular function with small molecule inhibitors of kinase activity, and thus represent good targets for drug design. In addition to methods for treating kinase-mediated diseases, selective and potent inhibitors of kinase activity are useful for studying cell signaling processes and identifying other therapeutically interesting cellular targets.

Ample evidence exists regarding the critical role of B cells in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics that deplete B cells such as Rituxan are effective against autoantibody-induced inflammatory diseases such as rheumatoid arthritis (Rastetter et al. Annu Rev Med 2004 55:477). Therefore, inhibitors of protein kinases that play a role in B cell activation should be useful therapeutic agents for B cell mediated disease pathologies such as autoantibody production.

Signaling through the B-cell receptor (BCR) controls a range of B-cell responses, including proliferation and differentiation into mature antibody-producing cells. The BCR is a key regulatory point of B cell activity and aberrant signaling can lead to dysregulated B cell proliferation and the formation of pathological autoantibodies, which lead to a variety of autoimmune and/or inflammatory diseases. Two non-receptor tyrosine kinases located membrane-proximal and immediately downstream of the BCR are spleen tyrosine kinase (SYK) and Bruton's protein tyrosine kinase (BTK). Lack of either of these kinases has been shown to block BCR signaling and therefore it is proposed that inhibition of one or both of these targets would be an effective therapeutic approach to block B cell mediated disease processes.

BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell formation as well as mature B cell activation and survival (Khan et al. Immunity 19953:283; Ellmeier et al. J. Exp. Med .2000 192:1611). BTK mutations in humans cause conditional X-linked agammaglobulinemia (XLA) (in Rosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol. Rev. 2005 203: 200 reviewed). These patients are immunocompromised and display impaired B-cell maturation, reduced immunoglobulin and peripheral B-cell levels, reduced T-cell-independent immune responses, and attenuated calcium mobilization following BCR stimulation.

Evidence for the role of BTK in autoimmune and inflammatory diseases has been provided by BTK-deficient mouse models. In a preclinical murine model of systemic lupus erythematosus (SLE), BTK-deficient mice showed a dramatic improvement in disease progression. Furthermore, BTK-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459).

BTK is also expressed by cells other than B cells that may be involved in the disease process. For example, BTK is expressed by mast cells and BTK-deficient bone marrow-derived mast cells show impaired antigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280:40261). This shows that BTK can be effectively used in the treatment of pathological mast cell responses such as allergy and asthma. Furthermore, monocytes from XLA patients in whom BTK activity is deficient show reduced TNFα production after stimulation (Horwood et al. J Exp Med 197:1603, 2003). Therefore, TNFα-mediated inflammation can be inhibited by small-molecule inhibitors of BTK. Furthermore, BTK has been reported to play a role in apoptosis (Islam and Smith Immunol Rev (Immunology Reviews) 178:49, 2000), and thus BTK inhibitors would be effective for the treatment of certain B-cell lymphomas and leukemias ( Feldhahn et al. J Exp Med 201:1837, 2005).

SYK is another non-receptor tyrosine kinase that is essential for B cell activation through BCR signaling. SYK is activated upon binding to phosphorylated BCR and thus triggers early signaling events following BCR activation. SYK-deficient mice display an early block in B cell formation (Cheng et al. Nature 378:303, 1995; Turner et al. Nature 378:298, 1995). Therefore, inhibition of SYK enzyme activity in cells is proposed to treat autoimmune diseases through its effect on autoantibody production.

In addition to the role of SYK in BCR signaling and B cell activation, it has also been shown to play a critical role in FcεRI-mediated mast cell degranulation and eosinophil activation. Thus, SYK has been implicated in allergic diseases, including asthma (reviewed in Wong et al., Expert Opin Investig Drugs 13:743, 2004). SYK binds to the phosphorylated gamma chain of FcεRI through its SH2 domain and is essential for downstream signaling (Taylor et al. Mol. Cell. Biol. 15:4149, 1995). SYK-deficient mast cells display defective degranulation, arachidonic acid and cytokine secretion (Costello et al. Oncogene 13:2595, 1996). Pharmaceutical agents that inhibit SYK activity in mast cells have also been shown to do so (Yamamoto et al. J Pharmacol Exp Ther 306:1174, 2003). Treatment with SYK antisense oligonucleotides inhibits antigen-induced infiltration of eosinophils and neutrophils in animal models of asthma (Stenton et al. J Immunol 169:1028, 2002). SYK-deficient eosinophils also display impaired activation in response to FcεR stimulation (Lach-Trifilieffe et al. Blood 96:2506, 2000). Therefore, small molecule inhibitors of SYK would be effective for the treatment of allergy-induced inflammatory diseases, including asthma.

SYK kinase inhibitors have been shown to inhibit mast cell degranulation in cell-based assays. (Lai et al, Bioorg.Med.Chem.Lett.2003 13:3111-3114; Moriya et al.Proc.Natl.Acad.Sci.USA 1997 94:12539-12544; Yamamoto et al.J.Pharmacol.Exp Ther.2003 306 (3): 1174-1181. SYK inhibitors were also shown to inhibit antigen-induced passive skin hypersensitivity, bronchoconstriction and bronchial edema in rats (Yamamoto, supra).

In WO2006/032518 published March 30, 2006, Boyd et al. teach that some examples of the phthalazinone compounds disclosed herein are effective as inhibitors of Aurora kinase for the treatment of cancer, and In particular colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, stomach cancer, bladder cancer, cranial cancer, neuroblastoma, cervical cancer, renal or kidney cancer and melanoma.

The present invention relates to a method of treating a disease mediated by a tyrosine kinase, wherein said tyrosine kinase is BTK or SYK, said method comprising administering a therapeutically effective amount of a compound according to formula I to a patient in need thereof

in

R ¹ , R ² and R ⁴ independently represent R ⁸ -X-, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² , hydrogen, halogen, nitro, cyano, -OH, - NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O)NH -OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _1-6 alkyl, -NHC(O)NH-OC _1-6 alkyl, -NHC(O)N (C _1-6 alkyl)-OC _1-6 alkyl, -S(O) ₂ NH-OC _1-6 alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _{1- 6} alkyl, or C _1-6 alkyl optionally substituted once or three times by halogen, hydroxy or alkoxy;

R ³ is R ⁸ -X-, R ⁹ -X ¹ -, R ⁸ -X ¹ (CH ₂ ) _m -, R ⁹ -X ¹ (CH ₂ ) _m -, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, hydrogen, halogen, nitro, cyano, -OH, -NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O)NH-OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _{1- 6} Alkyl, -NHC(O)NH-OC _1-6 Alkyl, -NHC(O)N(C _1-6 Alkyl)-OC _1-6 Alkyl, -S(O) ₂ NH-OC _{1 -6} alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _1-6 alkyl, or C _1-6 alkyl optionally substituted one or three times by halogen, hydroxyl or alkoxy base;

R ⁸ is C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² , aryl-T ³ -, heteroaryl-T ⁴ -, or C optionally substituted one to five times by halogen _1-6 alkyl;

R ⁹ is C _1-6 alkyl, wherein the alkyl is substituted one to three times by the following: hydroxyl, alkoxy, amino, C _1-6 alkylamino, C _1-6 dialkylamino, C _{1-6 6} Alkylthio, C _1-6 Alkylsulfinyl, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfamoyl, C _1-6 Dialkylsulfamoyl, C _1-6 Alkane Sulfonylamino or heterocyclylsulfonyl;

X is -C(O)NH-, -C(O)N(alkyl)-, -N(alkyl)C(O)-, -NHC(O)-, -NHC(O)NH-, - NHC(O)N(Alkyl)-, -OC(O)N(Alkyl)-, -NHS(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(Alkyl )-, -S(O) ₂ -, -S(O)-, -C(O)O-, -OC(O)-, -C(O)-, -NH-, -N(alkyl) -, -O- or -S-;

X ¹ is -S(O) ₂ -, -S(O)-, -OC(O)-, -C(O)-, -NH-, -N(alkyl)-, -O- or -S -;

T ¹ , T ² , T ³ and T ⁴ independently represent a single bond or an alkylene group optionally substituted once or twice by hydroxyl;

^R is hydrogen, C _1-6 alkyl optionally substituted one or several times by halogen or alkoxy, heteroaryl, or phenyl optionally substituted once or twice by : Halogen, -NO ₂ , -OH, -C(O)OH, -C(O)NH-aryl, -C(O)NH ₂ , -C(O)NH-C _1-6 alkyl, - C(O)N(C _1-6 alkyl) ₂ , -C(O)-heterocyclyl, -NH ₂ , -NHC(O)-aryl, -NHC(O)-C _3-7 cycloalkane Base, -NHC(O)-C _1-6 alkyl, -N(C _1-6 alkyl)C(O)-C _1-6 alkyl, -NHC(O)OC _1-6 alkyl,- N(C _1-6 alkyl)C(O)OC _1-6 alkyl, -NHC(O)-C _1-6 alkoxyalkyl, -NH-S(O) ₂ -aryl, -NH -S(O) ₂ -C _1-6 alkyl, -C(O)NH-S(O) ₂ -aryl, -C(O)NH-S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -alkyl, -NH-aryl, -O-aryl, -S(O)-aryl, aryl, heterocyclyl, C _3-7 cycloalkyl, C _1-6 Alkyl, C _1-6 alkoxy or C _1-6 alkylthio, said alkyl, alkoxy and alkylthio are optionally substituted once or three times by: halogen; optionally independently by one Naphthyl substituted by three halogens, phenyl independently substituted by three halogens; 1,3-dihydro-isobenzofuryl, benzo[1,3]dioxol-5- Base, C _3-7 cycloalkyl or C _1-6 alkenyl;

Y is an alkylene, alkylene-C(O)- or alkylene-CH(OH)-;

m is 1-5;

n is 0 or 1;

R is ^hydrogen , C _1-6 alkyl, cyano or halogen; and

R ⁷ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl;

or a medicinal salt thereof.

The tyrosine kinase inhibitors of formula I are useful in the treatment of allergy-induced inflammatory diseases. Diseases that may be alleviated by administration of a therapeutically effective amount of a compound of formula I include allergy-induced inflammatory diseases, including asthma, systemic lupus erythematosus and multiple sclerosis. The compounds of the present invention are also beneficial in the treatment of rheumatoid arthritis.

The compounds according to the invention show activity as protein kinase inhibitors. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been considerable effort in medicinal chemistry to discover protein kinase inhibitors that are effective as therapeutic agents.

The compounds according to the invention show in particular activity as BTK and SYK inhibitors and can therefore be useful in the treatment of diseases mediated by these kinases. Inhibition of BTK and/or SYK blocks B-cell receptor (BCR) signaling and resulting B-cell maturation and activation. This shows that BTK and SYK inhibitors are effective for the treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. In addition, inhibitors of SYK are particularly useful in the treatment of allergic inflammation, including asthma. Both kinases are associated with the regulation of apoptosis and can be used in the treatment of lymphoma or leukemia. In particular, BTK has recently been implicated in certain Philadelphia-positive cases of acute myelogenous leukemia (AML) and thus may be effective in treating certain subsets of AML patients.

The present invention includes methods of treating inflammatory and autoimmune diseases using compounds of formula I and all tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates thereof , their use as BTK and SYK inhibitors. For example, the pyrazole ring of formula I can exist in two tautomeric forms as shown below and the present invention includes the use of all tautomers in the treatment of inflammatory and autoimmune diseases:

The term "as defined above" refers to the broadest definition provided for each group in the broadest claim. In all other embodiments provided below, substituents which may be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.

As used herein, the term "a" or "an" an entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Accordingly, the terms "a" (or "an"), "one or more" and "at least one" may be used interchangeably herein.

In one embodiment of the present invention there is provided a method of treating diseases mediated by the tyrosine kinases BTK and/or SYK, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 , R 7 ,} R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n as above text definition.

In another embodiment of the present invention there is provided a method for the treatment of diseases mediated by tyrosine kinases BTK and/or SYK comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I , wherein R ¹ , R ² , R ⁴ and R ⁶ are hydrogen; R ³ is heterocyclyl-T ² , R ⁸ -X-, R ⁹ -X ¹ , H(O)CNH- or optionally hydroxy Substituted C _1-6 alkyl; R ⁸ is heterocyclyl-T ² ; heterocyclyl is piperidine, piperazine, N-methylpiperazine or morpholine; T ² is a single bond; X is -O- , -N(C _1-6 alkyl)-, -C(O)NH- or -C(O)N(C _1-6 alkyl)-; or n is 0 and R ⁵ is C _1-6 alkane or n is 1, Y is C _1-6 alkylene and R ⁵ is optionally substituted phenyl; R ⁷ is C _1-3 alkyl.

In another embodiment of the present invention there is provided a method for treating a disease mediated by BTK, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

In another embodiment of the present invention there is provided a method for the treatment of a disease mediated by SYK comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

In another embodiment of the present invention there is provided a method for the treatment of an allergy-induced inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

In another embodiment of the present invention there is provided a method for the treatment of asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

In another embodiment of the present invention there is provided a method for the treatment of systemic lupus erythematosus or multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

In another embodiment of the present invention there is provided a method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T ³ , T ⁴ , X, X ¹ , Y, m and n are as defined above.

As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1-6, preferably 1-4, more preferably 1 or 2 carbon atoms, such as methyl, ethyl, n-propyl base, isopropyl, n-butyl, 2-butyl, tert-butyl.

As used herein, the term "alkoxy" refers to an alkyl group as defined above attached through an oxygen atom.

As used herein, the term "alkylthio" refers to an alkyl group as defined above attached through a sulfur atom.

If the alkyl, alkoxy or alkylthio group is substituted once or several times by halogen, it is substituted 1-5 times, preferably 1-3 times, by chlorine or fluorine, preferably by fluorine. Examples are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trichloroethyl, 2-chloro-ethyl, 3-chloro- Propyl, etc., preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or perfluoroethyl. The term "haloalkyl" as used herein refers to an alkyl group as defined above substituted with 1-5 halo.

If the alkyl group is substituted once or several times by hydroxy or alkoxy, it is substituted by hydroxy or alkoxy one to three times, preferably 1-2 times. Examples are e.g. hydroxy-methyl, 2-hydroxy-butyl, 2-hydroxy-ethyl, 1-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-butyl, 2,3-dihydroxy- Propyl, 2,3-dihydroxy-butyl, 1,2,3-trihydroxy-propyl, 2-hydroxy-pentyl, methoxy-methyl, ethoxy-methyl, 2-methoxy Base-ethyl, 2-ethoxy-ethyl, 4-methoxy-butyl, 2-methoxy-butyl, 2-ethoxy-propyl, 3-propoxy-butyl, 2,3-Dimethoxy-propyl, 2-ethoxy-3-methoxy-propyl, 2,3-diethoxy-butyl, 1,2,3-trimethoxy-propyl base, 2-methoxy-pentyl, etc. The term "hydroxyalkyl" as used herein refers to an alkyl group as defined above substituted with 1-3 hydroxy groups.

As used herein, the term "alkylene" refers to a saturated straight or branched chain, preferably straight chain hydrocarbon containing 1-5, preferably 1-3 carbon atoms, such as methylene, ethylene , trimethylene (1,3-propylene); tetramethylene (butylene), pentamethylene, methyl-methylene, methyl-ethylene (1,2-propylene) , ethyl-ethylene, propyl-ethylene, 1-methyl-trimethylene, 2-methyl-trimethylene, 1-ethyl-trimethylene, 2-ethyl-trimethylene .

Preferably, Y represents methylene or ethylene, and more preferably methylene.

As used herein, the term "alkenyl" refers to an unsaturated straight or branched, preferably straight chain hydrocarbon comprising 2 to 6, preferably 2 to 4 carbon atoms. Examples of said "alkenyl" are ethenyl (vinyl), allyl, isopropenyl, 2-butenyl, 3-butenylene, 3-methyl-2-butenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenylene , preferably allyl.

The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine, more preferably fluorine and chlorine.

The term "aryl" as used herein refers to phenyl or naphthyl, eg 1-naphthyl, 2-naphthyl or 3-naphthyl and preferably refers to phenyl. The aryl can optionally be replaced by a) alkyl, b) haloalkyl, c) halogen, preferably chlorine or fluorine, d) cyano, e) alkoxy, f) haloalkoxy, g) -C (O)-Alkyl, preferably acetyl, h) alkylsulfonyl, i) hydroxyl, j) amino or k) nitro are substituted one to three times, preferably one or two times. Preferably, the aryl is optionally substituted with a) alkyl, b) haloalkyl, c) halo, d) cyano, e) alkoxy, f) haloalkoxy or i) hydroxy. More preferably, aryl is optionally substituted with a) alkyl, b) haloalkyl, c) halo, d) cyano, e) alkoxy, f) haloalkoxy or i) hydroxy. In one embodiment of the invention, the aryl group defined in R ⁸ is optionally substituted one to three times as described above, while the aryl group in R ⁵ is unsubstituted. Even more preferably all aryl groups are unsubstituted. Examples of substituted aryl groups are e.g. 4-methyl-phenyl, 3-methyl-phenyl, 2-methyl-phenyl, 4-chloro-phenyl, 3-chloro-phenyl, 2-chloro- Phenyl, 4-fluoro-phenyl, 2-fluoro-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethyl-2-fluoro-phenyl, 3-trifluoromethyl-phenyl , 4-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 4-amino-phenyl, 3-hydroxy- Phenyl, 4-acetyl-phenyl, 4-acetyl-2-methyl-phenyl, etc.

The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring having 5-10 ring atoms, which contains up to 3, preferably 1 or 2, heteroatoms independently selected from N, O or S and the remaining ring atoms are carbon atoms. The heteroaryl group may optionally be substituted one to three times, preferably one or two times, by a) alkyl, as defined above, preferably methyl, b) haloalkyl, c) halogen, preferably is chlorine or fluorine, d) cyano, e) alkoxy, f) haloalkoxy. Preferably, the heteroaryl is optionally substituted with a) alkyl, b) haloalkyl, c) halo, d) cyano, e) alkoxy, f) haloalkoxy or i) hydroxy. More preferably, the heteroaryl is optionally substituted with a) alkyl, b) haloalkyl, c) halo, d) cyano, e) alkoxy, f) haloalkoxy or i) hydroxy. Even more preferred, heteroaryl is optionally substituted with alkyl. Examples of said heteroaryl groups are thienyl, methylthienyl, pyrazolyl, dimethylisoxazolyl, pyridyl, benzothienyl, indolyl, furyl, pyrrolyl, imidazolyl, pyrimidine Base, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, methylthiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, quinone Linyl, isoquinolyl, benzofuryl, etc., preferably thiazolyl, methylthiazolyl, pyridyl, picoline, trifluoromethyl-pyridyl, pyrimidinyl, triazolyl, methyltri Azolyl or thiadiazolyl, more preferably pyridyl or methylthiazolyl.

The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3-7, preferably 3-5 ring atoms. The monocyclic saturated hydrocarbon ring may optionally be substituted one to three times, preferably one or two times, by an alkyl group, preferably a methyl group. Preferably, the cycloalkyl group is unsubstituted. Examples of said saturated carbocyclic groups are cyclopropyl, 1-methyl-cycloprop-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl-1 -yl, and cycloheptyl, preferably cyclopropyl, preferably cyclopropyl, cyclobutyl, and cycloheptyl, more preferably cyclopropyl.

The term "heterocyclyl" refers to a saturated monocyclic ring having 5-6 ring atoms containing up to 3, preferably 1 or 2 heteroatoms independently selected from N, O or S, and the remaining The ring atoms are carbon atoms. The saturated heterocyclic group may optionally be substituted one to three times, preferably once or twice, by: a) alkyl, as defined above, preferably methyl, b) -C(O)- Alkyl, preferably acetyl, c) oxo or d) -S(O) ₂ -alkyl. Preferably the heterocyclic group may be optionally substituted with an alkyl group. Examples of the saturated heterocyclic group are pyrrolidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl (or 1,1- Dioxo (dioxido-thiomorpholin-4-yl), piperazinyl, N-methyl-piperazinyl, N-acetyl-piperazinyl, 3-oxo-piperazin-1-yl, 2-oxo-piperazin-1-yl, piperidinyl, oxazolidinyl, thiazolidinyl, etc., preferably morpholinyl, piperazinyl, N-methyl-piperazinyl or N-acetyl- Piperazinyl, and especially preferably morpholinyl, N-methyl-piperazinyl or piperidinyl.

Abbreviations commonly used herein include: N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), di-iso-propylethylamine ( DIPEA), N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI ), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), acetic acid (HOAc), isopropanol (IPA), methanol (MeOH), melting point (mp), acetonitrile (MeCN), mass spectrum (ms or MS), N-methylpyrrolidone (NMP), positron electrospray ionization mode (ESI+), room temperature (RT), triethylamine (TEA or Et ₃ N), trifluoroacetic acid (TFA), tetrahydrofuran (THF ). Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo (neo) have their ordinary meanings when applied to alkyl moieties (Rigaudy and Klesney , Nomenclature in Organic Chemistry (Nomenclature in Organic Chemistry), IUPAC 1979 Pergamon Press, Oxford).

The term "pharmaceutically acceptable salt" is used as follows.

The term "therapeutically effective" or "therapeutically effective amount" as used herein refers to an amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, that significantly inhibits B cell proliferation and/or prevents B cell differentiation.

As used herein, referring to nuclear magnetic resonance (NMR), the term "D ₆ -DMSO" refers to deuterated dimethylsulfoxide; the term "CDCl ₃ " refers to deuterated chloroform; the term "C ₆ D ₆ " refers to deuterated benzene; and the term " _CD3OD " refers to deuterated MeOH.

Aminopyrazole derivatives of general formula I, or pharmaceutically acceptable salts thereof, may be prepared by any suitable method known to those skilled in the art for the preparation of chemically related compounds. Said process is provided as an additional feature of the invention when used in the preparation of aminopyrazole derivatives of formula I or pharmaceutically acceptable salts thereof, and is illustrated by the following schemes 1, 2, 3, 4, 5 and 6, wherein Unless otherwise indicated, R ¹ , R ² , R 3 , R ^{4 ,} R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T ¹ , T ² , T 3 , ^{T 4 ,} X, X ¹ , Y, n, has the meaning given above. Necessary starting materials can be obtained by standard methods of organic chemistry. The preparation of such starting materials is described in the accompanying non-limiting examples. Alternatively, the necessary starting materials can be obtained by methods similar to those exemplified, which methods are within the ordinary skill of the organic chemist.

plan 1

The method for the synthesis of compounds of formula I starts from the corresponding phthalazinediones of formula II. Step 1 of the reaction sequence (Scheme 1) is a two-step process in which dibromination is followed by monohydrolysis to produce 4-bromo-2,3-naphthyridine derivatives of formula III. The first step (dibromination) is typically between 30°C and 150°C without solvent, or in solvents such as dichloromethane (DCM), dichloroethane (DCE), anisole, and mixtures thereof. at a temperature between. Typically used brominating agents are phosphorus oxybromide, phosphorus pentabromide, and phosphorus tribromide. The second step (monohydrolysis of the dibromide) is typically in a solvent such as water, aqueous lithium hydroxide, aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate , potassium carbonate in water, methanol in water (MeOH), glacial acetic acid (HOAc), at temperatures between 20°C and 110°C, under aqueous or anhydrous conditions.

In scheme 1, step 2, the obtained compounds of formula III are converted into their corresponding tertiary amides of formula VII using methods well known to those skilled in the art, such as alkylation under basic conditions. The reaction is typically in an aprotic solvent such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and mixtures thereof at -78 at temperatures between 100°C and 100°C. Typical bases used are sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, hexamethyldisilazide alkyl potassium together with alkylating agents such as alkyl halides, alkyl methanesulfonates and alkyl triflates. Under Mitsunobu reaction conditions, e.g. in the presence of diethyl azodicarboxylate and triphenylphosphine, typically in a solvent such as THF or DCM at room temperature (RT), alcohols can also be substituted for alkanes in step 2. agent.

In Scheme 1, step 3, phthalic anhydride derivatives of formula IV are converted to their corresponding phthalazines of formula VI with appropriate hydrazine derivatives using methods well known to those skilled in the art ketone. The reaction is typically performed at temperatures between 0°C and 120°C in aprotic solvents such as THF, DMF, NMP or protic solvents such as HOAc, ethanol (EtOH), MeOH and isopropanol (IPA) and mixtures thereof. Typically used hydrazine derivatives are aliphatic or aromatic hydrazines, and salts thereof such as phenylhydrazine hydrochloride, methylhydrazine hydrochloride, benzylhydrazine and isopropylhydrazine hydrochloride, which can be readily obtained from this prepared by those skilled in the art.

In Scheme 1, step 4, phthalic anhydride derivatives of formula IV are converted to their corresponding N-aminophthalic acid derivatives of formula V with appropriate hydrazine derivatives using methods well known to those skilled in the art imine. The reaction is typically performed at temperatures between 0°C and 120°C in aprotic solvents such as THF, DMF, NMP or protic solvents such as HOAc, EtOH, MeOH and IPA and mixtures thereof. Typically used hydrazine derivatives are aromatic hydrazines, and their salts, such as 2-chlorophenylhydrazine, 3-nitrophenylhydrazine, 4-nitrophenylhydrazine, and 4-carboxyethylphenylhydrazine, which can be readily prepared by those skilled in the art.

In Scheme 1, step 5, the obtained compounds of formula V are converted to their corresponding phthalazinones of formula VI using methods well known to those skilled in the art, such as ring expansion. The reaction is typically performed in protic solvents such as glycerol, sulfuric acid and HCl at temperatures between 100°C and 160°C.

In Scheme 1, step 6, the compounds of formula VI obtained are converted to their The corresponding phthalazinones of formula VII.

In Scheme 1, step 7a, the obtained compounds of formula VII are converted to their corresponding Aminopyrazole I. The reaction is typically carried out in solvents such as THF, dioxane, toluene, alkanols such as MeOH, EtOH, IPA, and mixtures thereof at temperatures between 40°C and 110°C. Bases typically used are cesium carbonate, triethylamine (TEA), sodium tert-butoxide and reagents such as palladium acetate, palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium tetrakis-triphenylphosphine may be used , bis-triphenylphosphinepalladium dichloride and phosphine-based ligands such as 2,2'-bis(diphenylphosphino)-1.1'-binaphthyl, 4,5-bis(diphenylphosphino) -9,9-dimethylxanthene and 2-(di-tert-butylphosphino)biphenyl, resulting in a suitably coordinated palladium(0) species.

Alternatively, compounds of formula I are obtained from compound VII in a two-step process:

In Scheme 1, step 7b, the compound of formula VII is converted to the corresponding protected aminopyrazole I- protected. In formula I-protected and VIII-a, PG represents a protecting group such as tert-butyl or p-methoxybenzyl or tert-butoxycarbonyl, which is attached to the pyrazole ring via N-1 or N-2.

In Scheme 1, step 8, the protecting group PG in the formula I-protected compound is cleaved to give the aminopyrazole I. This can be done by standard deprotection methods such as heating in the presence of an acid such as formic acid or HCl. If the protecting group PG is tert-butoxycarbonyl, cleavage may already take place during the work-up of reaction step 7b.

A preferred method for ^the synthesis of derivatives of formula I is described in Scheme 2, wherein R is phenyl substituted with -NH _or -NH-R' at the para or meta position, and R 'is -C(O)-aryl, -C(O)-cycloalkyl, -C(O)-alkyl, -C(O)-alkoxyalkyl, -S(O) ₂ -aryl radical, -S(O) ₂ -alkyl. In Scheme 2, a derivative of formula I is named Ia, wherein R is ^phenyl substituted at the para or meta position by -NH-R', and R' is -C(O)-aryl, - C(O)-cycloalkyl, -C(O)-alkyl, -C(O)-alkoxyalkyl, -S(O) ₂ -aryl, -S(O) ₂ -alkyl.

Scenario 2

The method for carrying out the synthesis of compounds of formula I-a starts from the corresponding nitrophenyl derivatives of formula VII-a. In Scheme 2, Step 1, the obtained compounds of formula VII-a (see Scheme 1) are converted to their corresponding anilines of formula IX using methods well known to those skilled in the art, for example by reduction of nitrobenzene to form anilines. The reaction is typically performed in solvents such as DMF, NMP, acetonitrile (MeCN), HOAc, EtOH and MeOH, and mixtures thereof, at temperatures between 20°C and 100°C. Typical reducing agents used are tin(II) chloride, tin(II) chloride monohydrate, ferric chloride.

In scheme 2, step 2, the obtained compounds of formula IX are converted into their corresponding amides of formula X, sulfonamide or urea. The reaction is typically performed in an aprotic solvent such as DCM, EtOH, THF, DMF, DMSO, NMP and mixtures thereof at temperatures between 0°C and 80°C. Typical bases used are TEA, DIPEA, pyridine, potassium carbonate and 4-(dimethylamino)pyridine (DMAP).

In Scheme 2, Step 3, the obtained compounds of formula X are converted to their corresponding aminopyrazoles Ia using the procedure described for Scheme 1, Step 7a.

In Scheme 2, step 4, the brominated phthalazinone compounds of formula VII-a are converted to their The corresponding aminopyrazoles XI.

In Scheme 2, step 5, the obtained compounds of formula XI are converted to their corresponding anilines of formula XII as described for step 1 of scheme 2 using methods well known to those skilled in the art.

In Scheme 2, step 6, the obtained compounds of formula XII are converted into their corresponding bis-amides, -sulfonamides or -ureas of formula XIII using the method described for step 2 of scheme 2.

In scheme 2, step 7, the obtained compounds of formula XIII are converted to their corresponding formula la amides, sulfonamides or ureas. The reactions are typically carried out in protic solvents such as water, MeOH and EtOH or aprotic solvents such as MeCN, DCM, THF, DMF, NMP and mixtures thereof at temperatures between 0°C and 80°C. Typical bases used are ammonia, potassium hydroxide, sodium hydroxide and lithium hydroxide.

A preferred method for the synthesis of derivatives ^of formula I is described in Scheme 3, wherein R is phenyl substituted in the ortho or meta position by -COOH or -C(O)-R", R" is -NH -aryl, -NH ₂ , -NH-alkyl, -N(alkyl) ₂ , -heterocyclyl, -NH-S(O) ₂ -aryl, -NH-S(O) ₂ -alkyl . In Scheme 3, the derivative of formula I is referred to as Ib, wherein R is ^phenyl substituted by -C(O)-R' at the para or meta position, and R' is -NH-aryl, - NH ₂ , -NH-alkyl, -N(alkyl) ₂ , -heterocyclyl, -NH-S(O) ₂ -aryl, -NH-S(O) ₂ -alkyl.

Option 3

Methods for the synthesis of compounds of formula I-b start from the corresponding carboxyalkyl derivatives of formula VII-b. In scheme 3, step 1, the obtained compounds of formula VII-b (see scheme I) are converted into their corresponding formula Carboxylic acids of XIV. The reaction is typically carried out in solvents such as THF, EtOH and MeOH, water and mixtures thereof at temperatures between 20°C and 60°C. Typical hydrolysis reagents used are lithium hydroxide, sodium hydroxide and potassium hydroxide.

In Scheme 3, step 2, the obtained compounds of formula XIV are converted to their corresponding carboxamides or acyl sulfonamides of formula XV using methods well known to those skilled in the art, such as acylation of amines and sulfonamides. The reaction is typically performed in an aprotic solvent such as DCM, EtOH, THF, DMF, DMSO, NMP and mixtures thereof at temperatures between 0°C and 80°C. Typical coupling agents used are N, N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) , O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate. The reaction can be carried out in the absence or presence of a base. Typical bases used are TEA, DIPEA, pyridine, potassium carbonate and DMAP.

In Scheme 3, step 3, the obtained compounds of formula XV are converted to their corresponding aminopyrazoles Ib as described for step 7a of scheme 1 using methods well known to those skilled in the art.

In Scheme 3, step 4, the brominated phthalazinone compounds of formula VIIb are converted to their corresponding aminopyridines as described for step 7a of scheme 1 using methods well known to those skilled in the art Azole XVI.

In Scheme 3, step 5, the obtained compounds of formula XVI are converted to their corresponding carboxylic acids of formula XVII as described for step 1 of scheme 3 using methods well known to those skilled in the art.

In scheme 3, step 6, the obtained compounds of formula XVII are converted to their corresponding formula Carboxamides or acylsulfonamides of Ib.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ to R ⁴ is -NH ₂ or R ⁸ -X ^I -, wherein X ^I is -NH- or -NH(alk group)-, one of ^R1 to ^R4 is R"', wherein R"' is as defined for ^R1 to ^R4 of formula I above, and the remaining two of ^R1 to ^R4 are hydrogen. In Scheme 4, the derivative of formula (I) is called Ic, wherein one of R ¹ to R ⁴ is R ⁸ -X ^I -, wherein X ^I is -NH- or -NH(alkyl)-, R One of ¹ to R ⁴ is R"', wherein R"' is as defined for R ¹ to R ⁴ of formula I above, and the remaining two of R ¹ to R ⁴ are hydrogen.

Option 4

The method for the synthesis of compounds of formula I-c starts from the corresponding naphthyridines of formula II-a. Step 1 of the reaction sequence (Scheme 4) is a two-step process in which dibromination is followed by monohydrolysis to give 4-bromo-nitronaphthyridine derivatives of formula XVIII. The procedure was performed as described in step 1 of protocol 1.

In scheme 4, step 2, the compounds of formula XVIII obtained are converted into their corresponding formula Tertiary amides of XIX.

In Scheme 4, step 3, the compounds of formula XIX obtained are converted to their corresponding compounds of formula XX by reducing nitrobenzene to form aniline as described in step 1 of scheme 2, using methods well known to those skilled in the art. aniline.

In Scheme 4, step 4, the obtained compounds of formula XX are converted to their corresponding secondary or tertiary amines of formula XXI using methods well known to those skilled in the art, such as alkylation of amines. The reaction is typically carried out in an aprotic solvent such as THF, DMF, DMSO, NMP and mixtures thereof at temperatures from -78°C to 100°C. Typical bases used are potassium carbonate, sodium hydride, potassium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide.

Ultimately, it is necessary to introduce an intermediate N protecting group such as tert-butoxycarbonyl (BOC), which is cleaved after the alkylation step to obtain the monoalkylated amine. If desired, these monoalkylated amines can be used as educts for the second alkylation step (see also schemes 7 and 8 for the introduction/deprotection of the BOC-group).

In scheme 4, step 5, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromide, vinyl bromide or aryl bromide as described for step 7a of scheme 1, The brominated phthalazinone compounds of formula XXI are converted to their corresponding aminopyrazoles Ic.

A method for the synthesis of derivatives of formula I is described in Scheme 5, one of R ¹ to R ⁴ is R ⁸ -X ^II -, wherein X ^II is -C(O)NH-, -NHC(O)NH - or -S(O) ₂ NH-, one of R ¹ to R ⁴ is R"', wherein R"' is as defined above for R ¹ to R ⁴ of formula I, and the remaining R ¹ to R ⁴ Two are hydrogen. In Scheme 5, the derivative of formula I is called Id, wherein one of R ¹ to R ⁴ is R ⁸ -X ^II -, wherein X ^II is -C(O)NH-, -NHC(O)NH - or -S(O) ₂ NH-, one of R ¹ to R ⁴ is R"', wherein R"' is as defined above for R ¹ to R ⁴ of formula I, and the rest of R ¹ to R ⁴ Two are hydrogen.

Option 5

The method for the synthesis of compounds of formula I-d starts from the corresponding naphthyridines of formula II-a. Steps 1 to 3 are the same as described in Scheme 4, leading to the corresponding amines of formula XX.

In Scheme 5, step 4, the obtained compound of formula XX is converted into Their corresponding amides, sulfonamides or ureas of formula XXII.

In Scheme 5, step 5, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromide, vinyl bromide or aryl bromide as described for step 7a of Scheme 1, The brominated phthalazinone compounds of formula XXII are converted to their corresponding aminopyrazoles Id.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ to R ⁴ is -C(O)OH or R ⁸ -X"'-, where X"' is -NHC(O) is described in Scheme 6 )-, -N(alkyl)C(O)- or -OC(O)-, one of R ¹ to R ⁴ is R"', wherein R"' is as above for R ¹ to R ⁴ of formula I defined, and the remaining two of ^R1 to ^R4 are hydrogen. In Scheme 6, the derivative of formula I is referred to as Ie, wherein one of R ¹ to R ⁴ is R ⁸ -X"'-, wherein X"' is -NHC(O)-, -N(alkyl )C(O)- or -OC(O)-, one of R ¹ to R ⁴ is R"', wherein R"' is as defined above for R ¹ to R ⁴ of formula I, and R ¹ to R ⁴ The remaining two are hydrogen.

Option 6

A preferred method for the synthesis of compounds of formula I-e starts from the corresponding naphthyridines of formula II-b. Step 1 of the reaction sequence (Scheme 6) is a two-step process in which monohydrolysis after dibromination produces 4-bromo-alkylcarboxy 2,3-naphthyridine derivatives of formula XXIII, as shown in Scheme 1 as described in step 1.

In scheme 6, step 2, the compounds of formula XXIII obtained are converted into their corresponding formula Tertiary amides of XXIV.

In Scheme 6, step 3, the obtained compounds of formula XXIV are converted to their The corresponding carboxylic acids of formula XXV.

In Scheme 6, step 4, the obtained compounds of formula XXV are converted to their corresponding formula Carboxamides, acylsulfonamides or carboxylic acid esters of XXVI.

In Scheme 6, step 5, the formula The brominated phthalazinone compounds of XXVI are converted to their corresponding aminopyrazoles Ie.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ to R ⁴ is R ⁸ X ^IV -, wherein X ^IV is -C(O)NH-, -NHC(O)NH- or -S(O) _2NH- and -C(O)N(alkyl)-, -NHC(O)N(alkyl)- or -S(O) _2N (alkyl)-, R to ^R4 One of them is R"', wherein R"' is as defined above for ^R1 to ^R4 of formula I, and the remaining two of ^R1 to ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl. In scheme 7 the derivative of formula I is named If, wherein one of R ¹ to R ⁴ is R ⁸ -X ^IV -, wherein X ^IV is -C(O)NH-, -NHC(O)NH- or -S(O) ₂ NH- and -C(O)N(alkyl)-, -NHC(O)N(alkyl)- or -S(O) ₂ N(alkyl)-, R ¹ to One of R ⁴ is R"', wherein R"' is as defined above for R ¹ to R ⁴ of formula I, and the remaining two of R ¹ to R ⁴ are hydrogen, R ⁶ is hydrogen, R ⁷ is methane base.

Option 7

A preferred method for the synthesis of compounds of formula I-f starts from the corresponding naphthyridines of formula II-a. Step 1 of the reaction sequence (Scheme 7) is a two-step process in which monohydrolysis after dibromination produces 4-bromo-nitro-2,3-naphthyridine derivatives of formula XVIII, as shown in Scheme 1 as described in step 1.

In scheme 7, step 2, the compounds of formula XVIII obtained are converted into their corresponding formula Tertiary amides of XIX.

In Scheme 7, step 3, the compounds of formula XIX obtained are converted to their corresponding compounds of formula XX by reducing nitrobenzene to form aniline as described in step 1 of scheme 2, using methods well known to those skilled in the art. aniline.

In Scheme 7, step 4, the obtained compounds of formula XX are converted to their corresponding secondary carbamates of formula XXVII using methods well known to those skilled in the art, such as tert-butoxycarbonylation of amines. The reaction is typically performed in solvents such as DMF, NMP, MeCN, DCM and DCE at temperatures between 0°C and 100°C. Typically used bases are imidazole, TEA, N,N-diisopropylethylamine (DIPEA) and N,N-dimethylamino-pyridine and reagents such as di-tert-butyl dicarbonate.

In Scheme 7, step 5, the obtained compounds of formula XXVII are converted to their corresponding tertiary carbamates of formula XXVIII using methods well known to those skilled in the art, such as alkylation of secondary carbamates. The reaction is typically performed in solvents such as DMF, NMP, MeCN, DCM and DCE at temperatures between 0°C and 100°C. Typical bases used are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with alkylating agents such as alkyl halides, Alkyl mesylate and alkyl triflate.

In Scheme 7, step 6, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromide, vinyl bromide or aryl bromide as described in step 7a of Scheme 1, the The obtained compound of formula XXVIII (obtained in step 5) or compound of formula XX (obtained in step 3) is converted into their corresponding aminopyrazoles of formula XXIX or formula XXXI.

In Scheme 7, Step 7, the obtained compounds of formula XXIX are converted to their corresponding anilines of formula XXX using methods well known to those skilled in the art, such as acid-mediated deprotection of boc-protected amines. The reaction is typically performed at temperatures between 0°C and 40°C in solvents such as DCM, dioxane, diethyl ether, dioxane and alkyl alcohols such as MeOH, EtOH and mixtures thereof. Typical acids used are anhydrous HCl, aqueous hydrochloric acid, TFA, trimethylsilyl bromide and trifluoromethanesulfonic acid.

In Scheme 7, step 8, a two-step approach is used in which monohydrolysis (of the acylated pyrazole-NH) is followed by diacylation (amine of formula XXX or XXXI and pyrazole-NH), yielding formula I-f Aminopyrazole derivatives, and the obtained compounds of formula XXX or formula XXXI are converted into their corresponding amides, sulfonamides or ureas of formula (I-f). The first step (diacylation) is typically in solvents such as DCM, dioxane and THF and mixtures thereof, at temperatures between 0°C and 80°C, using capping agents such as acid chlorides, anhydrides, sulfuryl chlorides and isocyanates. Typical bases used are TEA, DIPEA, and DMAP, potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide, which in Temperature between 0°C and 80°C. The second step (monohydrolysis of diamides, disulfonamides, diureas) is typically performed under aqueous conditions in solvents such as water, aqueous lithium hydroxide, aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium bicarbonate, sodium carbonate aqueous solution, aqueous potassium bicarbonate, aqueous potassium carbonate, at temperatures between 0°C and 80°C.

A preferred method for the synthesis of derivatives of formula I ^, wherein ^one of R ^to R is R ^{-X V} -, wherein X ^V is -N(alkyl)-, ^one of R to R is described in Scheme 7 is R"', wherein R"' is as defined above for ^R1 to ^R4 of formula I, and the remaining two of ^R1 to ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl. In Scheme 8, the derivative of formula I is called Ig, wherein one of R ¹ to R ⁴ is R ⁸ -X ^IV -, wherein X ^V is -N(alkyl)-, and one of R ¹ to R ⁴ is R"', wherein R"' is as defined above for ^R1 to ^R4 of formula I, and the remaining two of ^R1 to ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl.

Option 8

A preferred method for the synthesis of compounds of formula I-g starts from the corresponding naphthyridines of formula II-a. Step 1 of the reaction sequence (Scheme 8) is a two-step process in which monohydrolysis is carried out after dibromination to produce 4-bromo-nitro-2,3-naphthyridine derivatives of formula XVIII, as shown in Scheme 1 as described in step 1.

In scheme 8, step 2, the obtained compounds of formula XVIII are converted into their corresponding formula Tertiary amides of XIX.

In Scheme 8, step 3, the compounds of formula XIX obtained are converted to their corresponding compounds of formula XX by reducing nitrobenzene to form aniline as described in step 1 of scheme 2, using methods well known to those skilled in the art. aniline.

In Scheme 8, step 4, the obtained compounds of formula XX are converted to their corresponding Secondary carbamates of formula XXVII.

In Scheme 8, step 5, the obtained compounds of formula XXVII are converted into their corresponding Tertiary carbamates of formula XXVIII.

In Scheme 8, step 6, the obtained compounds of formula XXVIII are converted to their corresponding secondary compounds of formula XXXII using methods well known to those skilled in the art, such as deprotecting an acid-labile protecting group such as tert-butoxycarbonyl. amine. The reaction is typically performed without solvent, or in solvents such as diethyl ether, dioxane, THF, DCM and DCE or mixtures thereof, at temperatures between 0°C and 40°C. Typically used acids are HOAcTFA, trifluoromethanesulfonic acid, aqueous HCl, aqueous sulfuric acid or anhydrous hydrogen chloride.

In Scheme 8, step 7, the obtained compounds of formula XXXII are converted to their corresponding formula XXXIII using methods well known to those skilled in the art, such as alkylation of secondary amines as described for step 4 of scheme 4.

In Scheme 8, step 8, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromides, vinyl bromides or aryl bromides as described in Scheme 1, step 7a, will give Compounds of formula (XXXIII) are converted into their corresponding aminopyrazoles of formula I-g.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ to R ⁴ is -OH or R ⁸ -X ^VI -, wherein X ^VI is -O- or -C(O) is described in Scheme 9 O-, one of R ¹ to R ⁴ is R"', wherein R"' is as defined for R ¹ to R ⁴ of formula I above, and the remaining two of R ¹ to R ⁴ are hydrogen, R ⁶ is hydrogen and ^R7 is methyl. The derivative of formula (I) is called Ih in Scheme 9, wherein one of R ¹ to R ⁴ is R ⁸ -X ^IV -, wherein X ^IV is -O- or -C(O)O-, R ¹ one to ^R4 is R"', wherein R"' is as defined for ^R1 to ^R4 of formula I above, and the remaining two of ^R1 to ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl .

Option 9

A preferred method for the synthesis of compounds of formula I-h starts from the corresponding naphthyridines of formula II-a. Step 1 of the reaction sequence (Scheme 9) is a two-step process in which monohydrolysis is carried out after dibromination to produce 4-bromo-nitro-2,3-naphthyridine derivatives of formula XVIII, as shown in Scheme 1 as described in step 1.

In scheme 9, step 2, the obtained compounds of formula XVIII are converted into their corresponding formula Tertiary amides of KIX.

In Scheme 9, step 3, the compounds of formula XIX obtained are converted to their corresponding compounds of formula XX by reducing nitrobenzene to form aniline as described in step 1 of scheme 2, using methods well known to those skilled in the art. aniline.

In Scheme 9, step 4, the obtained compounds of formula (XX) are converted to their corresponding formula XXXIV using methods well known to those skilled in the art, such as diazotization of aniline and displacement of diazonium species with nucleophiles alcohol. The reaction is a two-step process, wherein step 1 is to generate diazotized species, and step 2 is to use nucleophiles to replace diazonium species. Step 1 of the reaction is typically performed in a solvent such as sulfuric acid, HCl or HOAc and mixtures thereof. Typically used reagents are sodium nitrite and isoamyl nitrite as well as additional reagents such as urea. The first step of the reaction is typically carried out at a temperature between -10°C and 30°C. Step 2 of the reaction is typically performed in an aqueous medium such as aqueous HCl, aqueous sulfuric acid and aqueous HOAc. The second step of the reaction is typically carried out at a temperature between 20°C and 130°C.

In Scheme 9, step 5, the obtained compounds of formula XXXIV are converted to their corresponding ethers of formula XXXV using methods well known to those skilled in the art such as alkylation of phenols. The reaction is typically performed in solvents such as DMF, THF, NMP, MeCN, acetone, DCM and DCE at temperatures between 0°C and 100°C. Typical bases used are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with alkylating agents such as alkyl halides, Alkyl mesylate and alkyl triflate.

In Scheme 9, step 6, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromide, vinyl bromide or aryl bromide as described for step 7a of Example 1 , converting the obtained compounds of formula XXXV into their corresponding aminopyrazoles of formula I-h.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ to R ⁴ is R ⁸ -S-, or R ⁸ X ^VII -, wherein X ^VII is -S(O)- is described in scheme 10 or -S(O) ₂ -, one of R ¹ to R ⁴ is R"', wherein R"' is as defined above for R ¹ -R ⁴ of formula I, and the remaining two of R ¹ to R ⁴ are hydrogen, ^R6 is hydrogen and ^R7 is methyl. In scheme 10, derivatives of formula I are referred to as Ii (for one of R ¹ to R ⁴ is R ⁸ -S-) or Ij (for one of R ¹ to R ⁴ is R ⁸ -X ^VII -), wherein One of R ¹ to R ⁴ is R ⁸ -S-, or R ⁸ -X ^VII -, wherein X ^VII is -S(O)- or -S(O) ₂ -, and one of R ¹ to R ⁴ is R "', wherein R"' is as defined above for ^R1 to ^R4 of formula I, and the remaining two of ^R1 to ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl.

Scheme 10

A preferred method for the synthesis of compounds of formula I-i and I-j starts from the corresponding naphthyridines of formula II-a. Step 1 of the reaction sequence (Scheme 10) is a two-step process in which monohydrolysis is carried out after dibromination to produce 4-bromo-nitro-2,3-naphthyridine derivatives of formula XVIII, as shown in Scheme 1 as described in step 1.

In scheme 10, step 2, the compounds of formula XVIII obtained are converted to their corresponding formula Tertiary amides of XIX.

In Scheme 10, step 3, the compounds of formula XIX obtained are converted to their corresponding compounds of formula XX by reducing nitrobenzene to form aniline as described in step 1 of scheme 2, using methods well known to those skilled in the art. aniline.

In Scheme 10, step 4, the obtained compounds of formula XX are converted to their corresponding sulfur compounds of formula XXXVI using methods well known to those skilled in the art, such as diazotization of aniline and replacement of diazonium species with nucleophiles alcohol. The reaction is a two-step process, wherein step 1 is to generate diazo species, and step 2 is to use nucleophiles to replace diazo species. Step 1 of the reaction is typically performed in a solvent such as sulfuric acid, HCl or HOAc and mixtures thereof. Typically used reagents are sodium nitrite and isoamyl nitrite as well as additional reagents such as urea. The first step of the reaction is typically carried out at a temperature between -10°C and 30°C. Step 2 of the reaction is typically performed in aqueous acid in the presence of a sulfur nucleophile such as _Na2S or O-ethyldithiocarbonic acid.

In Scheme 10, step 5, the obtained compounds of formula XXXVI are converted to their corresponding ethers of formula XXXVII using methods well known to those skilled in the art, such as alkylation of thiophenol. The reaction is typically performed in solvents such as DMF, THF, NMP, MeCN, acetone, DCM and DCE at temperatures between 0°C and 100°C. Typical bases used are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with alkylating agents such as alkyl halides, Alkyl mesylate and alkyl triflate.

In Scheme 10, step 6, the obtained Compounds of formula XXXVII are converted to their corresponding aminopyrazoles of formula I-i.

In Scheme 10, step 7, the obtained compounds of formula Ii are converted to their corresponding sulfoxides or sulfones of formula Ij using methods well known to those skilled in the art, such as oxidation of thioethers to sulfoxides or sulfones. The reaction is typically performed at temperatures between 0°C and 110°C in solvents such as THF, toluene, alkanols such as MeOH, EtOH, IPA and water and mixtures thereof. Typically used reagents are OXONE ^™ and m-chloroperbenzoic acid.

A preferred method for the synthesis of derivatives of formula I is described in scheme 11, wherein one of R ¹ -R ⁴ is alkyl, especially methyl, substituted by alkoxy, and one of R ¹ -R ⁴ is R "', wherein R"' is as defined for R ¹ -R ⁴ of formula I, and the remaining two of R ¹ -R ⁴ are hydrogen. In scheme 11, the derivative of formula I is called Ik, wherein one of R ¹ -R ⁴ is an alkyl group substituted by an alkoxy group, especially methyl, and one of R ¹ -R ⁴ is R"', R"' is as defined above for ^R1 - ^R4 of formula I, and the remaining two of ^R1 - ^R4 are hydrogen.

Scheme 11

A preferred method for the synthesis of compounds of formula I-k starts from the corresponding naphthyridines of formula II-b. Step 1 of the reaction sequence (Scheme 11) is a two-step process in which monohydrolysis after dibromination produces 4-bromo-alkylcarboxy 2,3-naphthyridine derivatives of formula XXIII, as shown in Scheme 1 as described in step 1.

In scheme 11, step 2, the compounds of formula XXIII obtained are converted to their corresponding formula Tertiary amides of XXIV.

In Scheme 11, step 3, the obtained compounds of formula XXIV are converted to their corresponding alcohols of formula XXXVIII using methods well known to those skilled in the art, such as reduction of esters to form alcohols. The reaction is typically carried out in solvents such as THF, dioxane, DCM and mixtures thereof at temperatures between 0°C and 100°C. A typically used reducing agent is lithium borohydride.

In Scheme 11, step 4, the obtained compounds of formula XXXVIII are converted to their corresponding ethers of formula XXXIX using methods well known to those skilled in the art, such as alkylation of alcohols. The reaction is typically performed in solvents such as DME, THF, NMP, MeCN, acetone, DCM and DCE at temperatures between 0°C and 100°C. Typical bases used are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with alkylating agents such as alkyl halides, Alkyl mesylate and alkyl triflate.

In Scheme 11, step 5, the obtained Compounds of formula XXXIX are converted to their corresponding aminopyrazoles of formula I-k.

Another preferred method for the synthesis of derivatives of formula I is described in scheme 12, wherein one of R ¹ -R ⁴ is an alkyl group, especially a methyl group, which is substituted by an alkoxy group, and R ¹ -R ⁴ One is R"', wherein R"' is as defined for R ¹ -R ⁴ of formula I, and the remaining two of R ¹ -R ⁴ are hydrogen. In scheme 12, the derivative of formula I is called Ik, wherein one of R ¹ -R ⁴ is alkyl, especially methyl substituted by alkoxy, and one of R ¹ -R ⁴ is R"', R"' is as defined above for ^R1 - ^R4 of formula I, and the remaining two of ^R1 - ^R4 are hydrogen.

Scheme 12

A preferred method for the synthesis of compounds of formula I-k starts from the corresponding naphthyridines of formula II-b. Step 1 of the reaction sequence (Scheme 12) is a two-step process in which monohydrolysis after dibromination produces 4-bromo-alkylcarboxynaphthyridine derivatives of formula XXIII, as shown in Scheme 1 as described in step 1.

In scheme 12, step 2, the compounds of formula XXIII obtained are converted to their corresponding formula Tertiary amides of XXIV.

In Scheme 12, step 3, the obtained compounds of formula XXIV are converted to their corresponding compounds of formula XXXVIII using methods well known to those skilled in the art, such as reduction of esters to form alcohols as described in step 3 of scheme 11 alcohol.

In Scheme 12, step 4, the obtained compounds of formula XXXVIII are converted to their corresponding alkyl bromides of formula XL using methods well known to those skilled in the art, such as interconverting alcohol functional groups into bromides. The reaction is typically carried out in solvents such as MeCN, THF, dioxane, DCM and mixtures thereof at temperatures between 0°C and 100°C. Typically used brominating agents are trimethylsilyl chloride together with lithium bromide, trimethylsilyl bromide, phosphorus tribromide, or carbon tetrabromide/triphenylphosphine.

In Scheme 12, step 5, the obtained compounds of formula XL are converted to their corresponding ethers of formula XXXIX using methods well known to those skilled in the art, such as alkylation of alcohols. The reaction is typically performed in solvents such as DMF, THF, NMP, MeCN, acetone, DCM and DCE at temperatures between 0°C and 100°C. Typically used bases are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with nucleophiles such as alcohols.

In Scheme 12, step 6, the obtained Compounds of formula XXXIX are converted to their corresponding aminopyrazoles of formula I-k.

As an alternative to the routes described in Scheme 11 and Scheme 12, compounds of formula I-k can be prepared via the N,N'-diprotected intermediates of formula XLV shown in Scheme 14.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ -R ⁴ is heterocyclyl-T ² , wherein said heterocyclyl contains at least one nitrogen and wherein said heterocyclic and connected through nitrogen, T ² is an alkylene group, one of R ¹ -R ⁴ is R"', wherein R"' is as defined above for R ¹ -R ⁴ of formula I, and the remaining two of R ¹ -R ⁴ is hydrogen, ^R6 is hydrogen and ^R7 is methyl. In scheme 13, the derivative of formula (I) is referred to as Il, wherein one of R ¹ -R ⁴ is heterocyclyl-T ² , wherein said heterocyclyl comprises at least one nitrogen and wherein said heterocyclyl Linked through nitrogen, ^T2 is an alkylene group, one of ^R1 - ^R4 is R"', wherein R"' is as defined above for ^R1 - ^R4 of formula I, and the remaining two of ^R1 - ^R4 are hydrogen, ^R6 is hydrogen and ^R7 is methyl.

Scheme 13

A preferred method for the synthesis of compounds of formula I-l starts from the corresponding naphthyridines of formula II-b. Step 1 of the reaction sequence (Scheme 13) is a two-step process in which monohydrolysis after dibromination produces 4-bromo-alkylcarboxy 2,3-naphthyridine derivatives of formula XXIII, as shown in Scheme 1 as described in step 1.

In scheme 13, step 2, the compounds of formula XXIII obtained are converted to their corresponding formula Tertiary amides of XXIV.

In Scheme 13, step 3, the obtained compounds of formula XXIV are converted to their corresponding compounds of formula XXXVIII using methods well known to those skilled in the art, such as reduction of esters to form alcohols as described in step 3 of scheme 11 alcohol.

In Scheme 13, step 4, the obtained compounds of formula XXXVIII are converted into their corresponding formula Alkyl bromide of XL.

In Scheme 13, step 5, the obtained compounds of formula XL are converted to their corresponding heterocyclylalkyl derivatives of formula XLI using methods well known to those skilled in the art, such as N-alkylation of nitrogen-containing heterocycles thing. The reaction is typically carried out in solvents such as DMF, THF, NMP, MeCN, acetone, DCM and DCE at temperatures between 0°C and 100°C. Typically used bases are potassium carbonate, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide together with nucleophiles such as secondary amines.

In Scheme 13, step 6, the obtained Compounds of formula XLI are converted to their corresponding aminopyrazoles of formula I-l.

A preferred method for the synthesis of derivatives of formula I, wherein one of R ¹ -R ⁴ is R ⁸ X ^III -, wherein X ^III is -NHC(O)-, -N(alkyl) is described in scheme 14 C(O)- or -OC(O)-, one of R ¹ -R ⁴ is R"', wherein R"' is as defined above for R ¹ -R ⁴ of formula I, and the remainder of R ¹ -R ⁴ Two of are hydrogen, ^R6 is hydrogen and ^R7 is methyl. In scheme 14, the derivative of formula I is called Im, wherein one of R ¹ -R ⁴ is R ⁸ -X ^III -, wherein X ^III is -NHC(O)-, -N(alkyl)C( O)- or -OC(O)-, one of R ¹ -R ⁴ is R"', wherein R"' is as defined above for R ¹ -R ⁴ of formula I, and the remaining two of R ¹ -R ⁴ One is hydrogen.

Scheme 14

A preferred method for the synthesis of compounds of formula I-m starts from the corresponding hydroxymethylbromophthalazinones of formula XXXVIII (see Schemes 11 and 12 for the preparation). In Scheme 14, step 1, the obtained compounds of formula XXXVIII are converted to their corresponding silyl ethers of formula XLII using methods well known to those skilled in the art, such as silyl protection of alcohols. The reaction is typically carried out in an aprotic solvent such as DCM, THF, DMF, DMSO, NMP and mixtures thereof at a temperature between 0°C and 40°C. Typically used reagents are silyl chlorides or silyl trifluoroformates such as tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl trifluoromethanesulfonate. Typical bases used are imidazole, TEA, pyridine and DMAP.

In scheme 14, step 2, palladium-mediated amination of imine bromide, vinyl bromide or aryl bromide as described in reaction 7a of scheme 1 using methods well known to those skilled in the art , converting the obtained compounds of formula XLII into their corresponding aminopyrazoles of formula XLIII.

In Scheme 14, step 3, the obtained compounds of formula XLIII are converted to their corresponding protected aminopyrazoles of formula XLIV using methods well known to those skilled in the art, such as carbamate protection of amines. The reaction is typically performed in a solvent such as THF, dioxane, DCM, DMF or NMP. Typical bases used are TEA, sodium hydride, DMAP, together with reagents such as di-tert-butyl dicarbonate at temperatures between 0°C and 100°C.

In Scheme 14, step 4, the obtained compounds of formula XLIV are converted to their corresponding alcohols of formula XLV using methods well known to those skilled in the art, such as fluoride-mediated deprotection of silyl ethers. The reaction is typically carried out in solvents such as THF, dioxane and DCM at temperatures between 0°C and 100°C. Typical reagents used are tetrabutylammonium fluoride, potassium fluoride, hydrogen fluoride-pyridine complex, and silica-supported tetrabutylammonium fluoride.

In Scheme 14, step 5, the obtained compounds of formula XLV are converted to their corresponding aldehydes of formula XLVI using methods well known to those skilled in the art, such as oxidation of alcohols. The reaction is typically performed in solvents such as DMF, NMP, DMSO, THF, dioxane and DCM at temperatures between 0°C and 100°C. Typically used reagents are pyridine-sulfur trioxide complex, Dess-Martin periodinane (DMP) or 2-iodoxybenzoic acid (IBX).

In Scheme 14, step 6, the obtained compounds of formula XLVI are converted to their corresponding carboxylic acids of formula XLVII using methods well known to those skilled in the art, such as oxidation of carboxaldehydes. The reaction is typically carried out in solvents such as DCM, THF, water and mixtures thereof at temperatures between 0°C and 40°C. Typical reagents used are sodium chloride, buffers such as sulfamic acid and phosphoric acid and radical traps such as isobutylene are used.

In Scheme 14, step 7, the obtained compounds of formula XLVII are converted to their corresponding formula XLVIII using methods well known to those skilled in the art, for example amide formation by acid-amine coupling as described in step 2 of scheme 3 carboxamide.

In Scheme 14, step 8, the obtained compound of formula XLVIII is converted to the compound of formula I-m using methods well known to those skilled in the art, such as acid-mediated deprotection of the carbamate as described in step 7 of scheme 7. compound.

A preferred method for the synthesis of derivatives of formula I wherein n is 1 and Y is -alkylene-C(O)- or -alkylene-CH(OH)- is depicted in Scheme 15. Derivatives of formula I wherein n is 1 and Y is -alkylene-C(O)- are referred to as I-n in Scheme 15, and those wherein n is 1 and Y is alkylene-CH(OH)- Derivatives of formula I are referred to as I-o.

Scheme 15

A preferred method for the synthesis of compounds of formula I-n and I-o starts from the corresponding phthalazinediones of formula II. Step 1 of the reaction sequence (Scheme 15) is a two-step process as described in Step 1 of Scheme 1, wherein dibromination is followed by monohydrolysis to produce 4-bromonaphthyridine derivatives of formula III things.

In scheme 15, step 2, using methods known to those skilled in the art, for example, alkylation with α-halocarbonyl compounds under basic conditions as described in step 2 of scheme 1, the obtained formula III The compounds are converted into their corresponding tertiary amides of formula XLIX.

In Scheme 15, step 3, using methods well known to those skilled in the art, such as palladium-mediated amination of imine bromides, vinyl bromides or aryl bromides as described in step 7a of Scheme 1, will give Compounds of formula XLIX are converted to their corresponding aminopyrazoles of formula I-n.

In Scheme 15, step 4, the obtained compounds of formula l-n are converted to their corresponding alcohols of formula l-o using methods well known to those skilled in the art, such as reduction of ketones to form alcohols. The reaction is typically carried out in solvents such as THF, dioxane, DCM and mixtures thereof at temperatures between 0°C and 100°C. Typical reducing agents used are lithium borohydride and others.

A preferred method for the synthesis of derivatives of formula I is described in Scheme 16, wherein ^R is phenyl substituted in the ortho or meta position by -N(alkyl)-R', and R' is -C( O)-aryl, -C(O)-cycloalkyl, -C(O)-alkyl, -C(O)-alkoxyalkyl, -C(O)-alkoxy, -S( O) ₂ -aryl, -S(O) ₂ -alkyl. In Scheme 16, a derivative of formula I in ^which R is phenyl substituted by -N(alkyl)-R' in the ortho or meta position is referred to as Ip, and R' is -C(O)-aryl, -C(O)-cycloalkyl, -C(O)-alkyl, -C(O)-alkoxyalkyl, -C(O)-alk Oxy, -S(O) ₂ -aryl, -S(O) ₂ -alkyl.

Scheme 16

Step 1 of Scheme 16 is carried out by standard methods known to those skilled in the art, for example with alkyl bromide or iodide or tosylate or mesylate, in the presence of a base such as sodium hydride, potassium tert-butoxide or DIPEA Alkylation of compounds of formula X (see Scheme 2) yields compounds of formula X-a. Suitable inert solvents are eg DMF, DMSO, NMP or THF and the reaction is carried out at a temperature in the range -20°C to 100°C.

Step 2 of scheme 16 is as scheme 1, the bromo-2 of formula X-a described in step 7b, the aminopyrazole of 3-naphthalene and the protection of formula VIII-a carry out Buchwald coupling (the step of scheme 1 7a), resulting in a protected phthalazinone-aminopyrazole derivative of formula I-p-protected.

Step 3 of Scheme 16 is the cleavage of the protecting group as described in Scheme 1, Step 8.

Preferably certain derivatives of formula I are synthesized according to scheme 17, wherein R is ^phenyl substituted by substituent R"" in meta or ortho position, R"" is aryl, or a nitrogen-containing hetero Cyclo, NH-alkyl, NH-aryl or alkylthio or arylthio. In Scheme 17, the derivative of formula I is referred to as Iq.

Scheme 17

In step 1a of Scheme 17, a halogen-substituted phthalazinone L, wherein Hal is iodine or bromine or chlorine or fluorine, is replaced by a substitution reaction of an aromatic halogen with a group R"" into compounds of formula LI. This can be done directly under basic conditions if the group R"" contains a strong nucleophile and the halogen is fluorine. More preferably, Hal is iodine, bromine or chlorine and R"" is introduced under transition metal catalysis by methods known to chemists skilled in the art. A typical reaction for this purpose is the Buchwald reaction, if R"' is a nitrogen-containing heterocyclyl, NH-alkyl, NH-aryl, or alkylthio or arylthio group attached through N. The conditions for carrying out the Buchwald reaction are the same as those described in Scheme 1, Step 7a. If R"" is an alkylthio or arylthio group, it can also be carried out under Ullman conditions, for example in the presence of a Cu catalyst such as copper iodide or copper powder, in a solvent such as quinoline, NMP or ethylene glycol, optionally in the presence of a base such as pyridine for a substitution reaction. The Ullman reaction is carried out at elevated temperatures from 60°C to 200°C. If R"" is an aryl group, which is best introduced under the conditions of the Suzuki coupling. In the Suzuki coupling, in the presence of a base such as sodium carbonate or potassium fluoride, the boronic acid derivative of R"" is prepared from palladium black or palladium phosphine A palladium-catalyzed reaction of a complex such as tetrakis-triphenylphosphine-palladium(0) with L. Suitable solvents are toluene, water, dioxane, THF, MeOH, EtOH, or mixtures thereof, and Suzuki coupled in from RT to a temperature of 150°C.

Step 2a of Scheme 17 is the bromination of phthalazinone derivatives of formula LI to give 4-bromonaphthyridine derivatives of formula LII. Apply the same conditions as described in protocol 1, step 6.

Step 3a of Scheme 17 is the Buchwald coupling of the brominated phthalazinone derivative LII with the protected aminopyrazole VIII-a to give the final product in a protected form, I-q-protected. Apply the same method and conditions as described in Protocol 1, step 7b.

Step 4 of Scheme 17 is to deprotect the derivative I-q-protected to obtain the final aminopyrazole derivative I-q. Apply the same conditions as described in protocol 1, step 8.

Step 1b of Scheme 17 is the substitution reaction of the halogen atom in the protected aminopyrazole derivative of formula I-r. It was performed using the same method and conditions as described in step 1a.

Step 2b of Scheme 17 is the bromination of naphthyridine L to give LIII and proceeds as described in Scheme 1, Step 6.

Step 3b of Scheme 17 is the Buchwald coupling of the brominated phthalazinone derivative LIII with the protected aminopyrazole VIII-a to give the protected form of the I-r-protected aminopyrazole derivative. Apply the same method and conditions as described for protocol 1, step 7b. For this step, Hal is preferably chlorine, so that only the bromine atom in LIII is selectively replaced during the Buchwald reaction.

Step 1c of Scheme 17 is the substitution reaction of the halogen atom in the unprotected aminopyrazole derivative of formula I-r. This is carried out using the same method and conditions as described in step 1a.

Step 3c of Scheme 17 is the Buchwald coupling of the brominated phthalazinone derivative LIII with the aminopyrazole VIII to give the aminopyrazole derivative I-r. Apply the same method and conditions as described in step 7a of protocol 1. For this step, it is preferred that Hal is chlorine in order to achieve selective substitution of only bromine atoms in LIII during the Buchwald reaction.

If the substituents R"" are alkylthio and arylthio groups, these sulfanyl groups can then be oxidized to the substituents -S( O) alkyl, -SO ₂ alkyl and -S(O) aryl, -SO ₂ aryl. The oxidation step may optionally be performed later in the sequence, eg after step 2a or after step 3a or after step 1b.

Another method for the synthesis of derivatives of formula I, wherein one of R ¹ -R ⁴ is NH ₂ or NO ₂ or R ⁸ -X ^II -, wherein X ^II is -C(O) is described in scheme 18 NH-, -NHC(O)NH- or -S(O) ₂ NH-, one of R ¹ -R ⁴ is R"', R"' is as defined above for R ¹ -R ⁴ of formula I and R The remaining two of ¹ - ^R4 are hydrogen. In scheme 18, the derivative of formula I is called Id, wherein one of R ¹ -R ⁴ is R ⁸ -X ^II -, wherein X ^II is -C(O)NH-, -NHC(O)NH- or -S(O) ₂ NH-, one of R ¹ -R ⁴ is R"', wherein R"' is as defined above for R ¹ -R ⁴ of formula I and the remaining two of R ¹ -R ⁴ are hydrogen. In scheme 18, the derivative of formula I is called Is, wherein one of R ¹ -R ⁴ is NO ₂ , and one of R ¹ -R ⁴ is R"', wherein R"' is as above for R of formula I ¹ - ^R4 are defined and the remaining two of ^R1 - ^R4 are hydrogen. In scheme 18, the derivative of formula I is called It, wherein one of R ¹ -R ⁴ is NH ₂ , and one of R ¹ -R ⁴ is R"', wherein R"' is as above for R of formula I ¹ -R ⁴ are defined, and the remaining two of R ¹ -R ⁴ are hydrogen.

Program 18

Step 1 of Scheme 18 is the reaction of a nitro-substituted phthalic anhydride of formula LIII with a substituted hydrazine to give a compound of formula LIV. Step 1 was performed as described in step 4 of protocol 1.

Step 2 of Scheme 18 is the rearrangement of a compound of formula LIV to a naphthyridine of formula LV and proceeds as described in Step 5 of Scheme 1 .

Step 3 of Scheme 18 is the bromination of phthalazinone LV to give 4-bromophthalazinone LVI and proceeds as described in Scheme 1, step 6.

Step 4 of Scheme 18 is the Buchwald reaction of bromo-2,3-naphthyridine LVI with protected aminopyrazole derivative VIII-a to produce a derivative of formula I-s-protected and as for Scheme 1, step Proceed as described in 7b.

Step 5a of Scheme 18 is the deprotection of the derivative I-s-protected to give the nitro-substituted derivative I-s and is carried out as described in Scheme 1, Step 8.

In step 6 of scheme 18, the obtained compounds of formula I-s-protected are converted into their corresponding Formula I-t-protected aniline. Alternatively, the nitro group can be reduced in solvents such as MeOH or THF by catalytic hydrogenation using palladium on carbon as catalyst at temperatures between 20°C and 100°C.

In step 7 of scheme 18, using methods well known to those skilled in the art, such as sulfonylation, acylation or aminocarboxylation of aniline as described in step 6 of scheme 2, the obtained aniline compound of formula I-t-protected into their corresponding formula I-d-protected amides, sulfonamides or ureas.

Step 5b of Scheme 18 is the deprotection of the derivative I-t-protected to give the amino-substituted derivative I-t and is carried out as described in Scheme 1, Step 8.

Step 5c of Scheme 18 is the deprotection of the derivative I-d-protected to give the substituted derivative I-d and is carried out as described in Scheme 1, step 8.

For some special cases, a different reaction sequence could alternatively include the step of generating monochloro derivatives of phthalazinediones instead of the usual monobromo derivatives, followed by direct Buchwald reaction with the appropriate aminopyrazole, Or a Buchwald reaction with the appropriate aminopyrazole after some intermediate steps (see eg Scheme 19).

Another method for the synthesis of derivatives of formula I is described in Scheme 19, wherein one of R ¹ -R ⁴ is NO ₂ , the remaining two of R ¹ -R ⁴ are hydrogen, R ⁵ is hydrogen and n is 0. In Scheme 19, the derivative of formula I is called Iu, wherein one of R ¹ -R ⁴ is NO ₂ , the remaining two of R ¹ -R ⁴ are hydrogen, R ⁵ is hydrogen and n is 0

Program 19

In step 1 of Scheme 19, the substituted phthalic anhydride [compound of formula (VI-a)] is converted using methods well known to those skilled in the art such as hydrazine-mediated ring expansion of phthalic anhydride are their corresponding phthalazinones of formula (II-c). The reaction is typically carried out in an aprotic solvent such as THF, DMF, NMP or a protic solvent such as HOAc, EtOH, MeOH and IPA and mixtures thereof, eg at a temperature between 0°C and 120°. Typically used reagents are hydrazine, hydrazine hydrate and hydrazine hydrochloride. (This method can also be used to obtain 2,3 ^- diazepines of formula I in which R is other than hydrogen when N-substituted hydrazines, hydrazine hydrates and hydrazine hydrochlorides are used instead and subsequent steps are carried out accordingly naphthalene).

In step 2 of scheme 19, the obtained compounds of formula (II-c) are converted to their corresponding dichloromides of formula (LVII) using methods well known to those skilled in the art, such as the formation of imine chlorides from secondary amides. 2,3-Naphthalene. The reaction is typically performed without solvent, or in solvents such as DCM, DCE and anisole, and mixtures thereof, at temperatures between 30°C and 150°C. Typically used chlorination reagents are _POCl3 , _PCl5 and _PCl3 in the presence or absence of bases such as pyridine, TEA and DIPEA.

In step 3 of scheme 19, the obtained compounds of formula (LVII) are converted into their corresponding aminopyrazoles (LVIII ). The reaction is typically carried out in solvents such as THF, pyridine, toluene, alkanols such as IPA or tert-butanol, and mixtures thereof, at temperatures between 40°C and 150°C.

In step 4 of Scheme 19, imine chlorides of formula (LVIII) are converted to their corresponding amides (I-u) using methods well known to those skilled in the art such as monohydrolysis of imine chlorides. The reaction is typically performed under aqueous or anhydrous conditions in solvents such as water, aqueous lithium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, aqueous potassium bicarbonate, aqueous potassium carbonate, aqueous MeOH, iced HOAc, at 20 °C and 110 °C. at temperatures between °C.

In Schemes 1-19 above, certain substituents on groups ^R1 - ^R4 and ^R5 may not be inert to the conditions of the synthetic sequence described above and may require protection by standard protecting groups known in the art. For example, an amino or hydroxy group can be protected as an acetyl or tert-butoxycarbonyl derivative. Alternatively, some substituents may be derived from others at the end of the reaction sequence. For example, compounds of formula I can be synthesized having nitro, ethoxycarbonyl, sulfonic acid substituents on the groups ^R1 - ^R4 and ^R5 which are finally converted by standard methods to amino-, Alkylamino-, dialkylamino-, acylamino-, alkylsulfonylamino, arylsulfonylamino substituents, or converted to formamide substituents, or converted to sulfonamide substituents.

The compounds according to the invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic bases or from organic or inorganic acids. Examples of base addition salts include those derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, quaternary ammonium hydroxides such as eg tetramethylammonium hydroxide. Examples of acid addition salts include those from inorganic acids such as HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid , those of methanesulfonic acid, ethanesulfonic acid, etc. Chemical modification of pharmaceutical compounds (ie, drugs) into salts is a well-known technique among medicinal chemists to obtain enhanced physical and chemical stability, hygroscopicity, fluidity and solubility of compounds. See, e.g. Stahl and Wermuth (editors), Handbook of Pharmaceutical Salts (Handbook of Pharmaceutical Salts), Verlag Helvetica Chimica Acta (VHCA), Zürich, (2002) or Bastin et al., Organic Proc. Res. Dev. 4 (2000) 427-435 .

Compounds of formula I may contain one or more chiral centers and may then exist in racemic or optically active form. Said racemates can be separated into enantiomers according to known methods. For example, diastereoisomeric salts which can be separated by crystallization are formed from racemic mixtures by reaction with optically active acids such as, for example, D- or L-camphorsulfonic acid. Alternatively, separation of enantiomers can also be obtained by using chromatography on commercially available chiral HPLC-phases.

The compounds of formula I and their pharmaceutically acceptable salts possess useful pharmacological properties. Said compounds have been found to exhibit activity as BTK and SYK inhibitors and also exhibit anti-B cell activation activity. Therefore, the compounds of the present invention are useful for the treatment and/or prevention of diseases known to have activation or overexpression of BTK and/or SYK, especially for the treatment and/or prevention of the above mentioned diseases. The compounds of the invention are shown to be active as inhibitors of BTK and/or SYK by the following biological assays.

Determination of IC for Bruton's Tyrosine Kinase (Btk) Inhibition ₅₀

The assay captures ^{radioactive33P} phosphorylation products by filtration. Interaction of Btk, a biotinylated SH ₂ peptide substrate (Src homology) with ATP results in phosphorylation of the peptide substrate. The biotinylated products are bound streptavidin sepharose beads. The bound, radiolabeled product used is detected by a scintillation counter.

Assay plates were 96-well polypropylene (Greiner) and 96-well 1.2 μm hydrophilic PVDF filter plates (Millipore). Concentrations reported here are final assay concentrations: 10-100 μM compound (Burdick and Jackson), 5-10 nM Btk enzyme (His-tagged, full-length), 30 μM peptide substrate (Biotin-Aca- AAAEEIYGEI-NH ₂ ), 100 μM ATP (Sigma), 8 mM Imidazole (Sigma, pH 7.2), 8 mM Glycero-2-phosphate (Sigma), 200 μM EGTA (Roche Diagnostics), 1 mM MnCl ₂ (Sigma), 20 mM MgCl ₂ (Sigma), 0.1 mg/ml BSA (Sigma), 2 mM DTT (Sigma), 1 μCi ³³ P ATP (Amersham), 20% Streptavidin Sepharose beads (Amersham), 50 mM EDTA (Gibco), 2M NaCl (Gibco), 2M NaCl w/ 1% phosphoric acid (Gibco), microscint-20 (PerkinElmer).

_IC50 determinations were calculated from 10 data points for each compound using data generated from a standard 96-well plate assay template. One control compound and seven unknown inhibitors were tested on each plate in duplicate. Typically, compounds are diluted in half-log, starting at 100 [mu]M and ending at 3 nM. The control compound was staurosporine. Background was counted in the absence of peptide substrate. Total activity was determined in the presence of the peptide substrate. BTK inhibition was determined using the following method.

1) Sample preparation: Test compounds were diluted in assay buffer (imidazole, glycerol-2-phosphate, EGTA, _MnCl2 , _MgCl2 , BSA) in semi-log increments.

2) Bead preparation

a.) Rinse the beads by centrifugation at 500g

b.) Reconstitute the beads with PBS and EDTA to produce a 20% bead slurry

3) Pre-incubation of reaction mixture without substrate (assay buffer, DTT, ATP, ³³ P ATP) and with substrate (assay buffer, DTT, ATP, ³³ P ATP, peptide substrate) at 30°C ) for 15 minutes.

4) To initiate the assay, 10 μL of BTK in enzyme buffer (imidazole, glycerol-2-phosphate, BSA) and 10 μL of test compound were pre-incubated for 10 minutes at room temperature.

5) Add 30 [mu]L of the reaction mixture with or without substrate to BTK and compound.

6) Incubate 50 μL of total assay mixture at 30° C. for 30 minutes.

7) Stop the reaction by transferring 40 μL of assay to 150 μL of bead slurry in a filter plate.

8) After 30 minutes, wash the filter plate with the following steps:

a. 3×250μL NaCl

b. 3 x 250 μL NaCl containing 1% phosphoric acid

c.1× _250μL H2O

9) Dry the plate at 65°C for 1 hour or at room temperature overnight

10) Add 50 μL of microscint-20 and count ³³ P cpm on a scintillation counter. Calculation of percent activity from raw data expressed in cpm

Percent activity=(sample-bkg)/(total activity-bkg)×100

Calculation of _IC50 from percent activity using a one-site dose-response sigmoidal model

y=A+((BA)/(1+((x/C) ^D ))))

x = compound (cmpd) concentration, y = % activity, A = min, B = max, C = _IC50 , D = 1 (Hill slope)

Using the compounds of the invention, _IC50s for BTK inhibition were detected in the range of 0.14-0.88 [mu]M (13 compounds) and 1.1-65 [mu]M (45 compounds). Representative results are in Table 1.

Determination of IC for spleen tyrosine kinase (SYK) inhibition ₅₀

The SYK kinase assay is a standard kinase assay adapted to a 96-well plate format. The assay was performed in a 96-well format for the _IC50 determination of 8 samples representing 10 half-log dilutions and a 40 μL reaction volume. The assay measures the binding of radiolabeled ^33P γATP to an N-terminally biotinylated peptide substrate derived from the consensus sequence of naturally occurring phosphoacceptors (biotin-11aa DY*E). Phosphorylated products were detected after stopping the reaction with EDTA and adding streptavidin-coated beads.

Assay plate: 96-well MultiScreen 0.65um filter plate (Millipore catalog number: MADVNOB10)

Streptavidin-coated beads: Streptavidin Sepharose™, suspension 5.0 mL in 50 mM (1:100) diluted EDTA/PBS, (Amersham, catalog number: 17-5113 -01)

Compound: 10 mM in 100% dimethyl sulfoxide (DMSO), final concentration: compound 0.003-100 uM in 10% DMSO

Enzyme: SYK RPA, purified truncated construct aa 360-635 of spleen tyrosine kinase, stock solution 1 mg/mL, MW: 31.2 KDa, final concentration: 0.0005 μΜ.

Peptide 1: Biotinylated peptide from naturally occurring phospho-receptor consensus sequence (Biotin-EPEGDYEEVLE), specially ordered from QCB, stock solution 20 mM, final concentration: 5.0 μΜ.

ATP: Adenosine-5'-triphosphate 20 mM, (ROCHE catalog number: 93202720), final concentration: 20 μM

Buffer: HEPES: 2-Hydroxyethylpiperazine-2-ethanesulfonic acid (Sigma, catalog number: H-3375) Final concentration: 50 mM HEPES pH7.5

BSA: Bovine Serum Albumin Fraction V, fatty acid free (Roche Diagnostics GmbH, cat. no. 9100221 ), diluted to final concentration: 0.1%

EDTA: EDTA stock solution 500 mM, (GIBCO, catalog number: 15575-038) final concentration: 0.1 mM

DTT: 1,4-Dithiothreitol (Roche Diagnostics GmbH, catalog number: 197777), final concentration: 1 mM MgCl2 _{x 6H2O} : MERCK, catalog number: 105833.1000, final concentration: 10 mM

Assay dilution buffer (ADB): 50mM HEPES, 0.1mM EGTA, 0.1mM sodium vanadate, 0.1mM β-glycerophosphate, 10mM MgCl ₂ , 1mM DTT, 0,1% BSA, pH 7.5

Bead washing buffer: 10g/L PBS (phosphate buffered saline), containing 2M NaCl+1% phosphoric acid

Experimental method :

In a volume of 40 μL, mix 26 μL of ADB diluted, purified recombinant human SYK360-635 [0.5 nM] with 4 μL of a 10X concentration of test compound [typically 100 μM-0.003 μM] in [10%] DMSO and mix the mixture Incubate for 10 min at RT.

Kinase reactions were initiated by adding 10 μL of 4x substrate mix containing DYE peptide substrate [0 or 5 μM], ATP [20 μM] and ³³ PγATP [2 μCi/rxn]. After incubation for 15 minutes at 30°C, the reaction was terminated by transferring 25 μL of the reaction sample to a 96-well 0.65um Millipore MADVNOB membrane/plate containing 200 μL of 5 mM EDTA and 20% streptavidin in PBS protein-coated beads.

Unbound radionuclides were washed with 3 x 250 μL 2M NaCl; 2 x 250 μL 2M NaCl + 1% phosphoric acid; 1 x 250 μL _H2O under vacuum. After transferring the last washed membrane/plate into the backing plate, heat dry at 60 °C for 15 min, and add 50 μL of scintillation mix to each well, after 4 h, count the radioactivity in a top counter amount.

Calculate percent inhibition based on the ratio of uninhibited enzyme:

% inhibition=100/(1+( _IC50 /inhibitor concentration) ⁿ )

_IC50s were calculated using nonlinear curve fitting of XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK). Using the claimed compounds, _IC50s for SYK inhibition were detected in the range of 0.04-0.96 [mu]M (11 compounds) and 1.2-87 [mu]M (38 compounds). Representative results are in Table 1.

Inhibition of B-cell activation in Ramos cells - B cell FLIPR assay

Inhibition of B-cell activation by compounds of the invention was demonstrated by determining the effect of test compounds on anti-IgM stimulated B-cell responses.

The B-cell FLIPR assay is a cell-based functional method to determine the effect of potential inhibitors on the increase in intracellular calcium induced by anti-IgM antibody stimulation. Ramos cells (human Burkitt's lymphoma cell line. ATCC-No. CRL-1596) were cultured in growth medium (described below). The day before the assay, Ramos cells were resuspended in fresh growth medium (same as above) and placed in tissue culture flasks at a concentration of 0.5 x ¹⁰⁶ /mL. On the day of the assay, cells were counted and plated at a concentration of 1 x 10 ⁶ /mL in tissue culture flasks supplemented with 1 μM FLUO-3AM (TefLabs cat #0116 in anhydrous DMSO and 10% block polyether acid (Pluronic acid)) and incubated at 37°C (4% CO ₂ ) for 1 hour. To remove extracellular dye, cells were harvested by centrifugation (5 min, 1000 rpm) and resuspended in FLIPR buffer (described below) at 1 x ¹⁰ cells/mL, followed by dispensing at 1 x ¹⁰ cells/well at 96 - Wells in poly-D-lysine coated black/clear plates (BD Cat# 356692). Test compounds were added at seven concentrations ranging from 100 μΜ to 0.03 μΜ and allowed to incubate with cells for 30 minutes at room temperature. Ramos cell ^Ca signaling was stimulated by the addition of 10 μg/mL anti-IgM (Southern Biotech, cat. no. 2020-01) and measured on a FLIPR (Molecular Devices) using a CCD camera with an argon laser excited at 480 nM Capture images of 96-well plates).

Growth medium: RPMI 1640 medium containing L-glutamine (Invitrogen, catalog number 61870-010), 10% fetal bovine serum (FBS, Summit Biotechnology catalog number FP-100-05); 1 mM sodium pyruvate ( Invitrogen Cat. No. 11360-070).

FLIPR Buffer: HBSS (Invitrogen, Cat. No. 141175-079), 2 mM CaCl ₂ (Sigma, Cat. No. C-4901), HEPES (Invitrogen, Cat. No. 15630-080), 2.5 mM Probenecid (Sigma, Cat. No. P- 8761), 0.1% BSA (Sigma, Cat. No. A-7906), 11 mM Glucose (Sigma, Cat. No. G-7528).

To obtain the highest final assay concentration of 100 μM, 24 μL of a 10 mM compound stock solution (prepared in DMSO) was added directly to 576 μL of FLIPR buffer. Test compounds were diluted in FLIPR buffer (using a Biomek 2000 automatic pipette) to obtain the following dilution scheme: Excipient, 1.00×10 ⁻⁴ M, 1.00×10 ⁻⁵ , 3.16×10 ⁻⁶ , 1.00×10 ^{−6 6} , 3.16×10 ^-7 , 1.00×10 ^-7 , 3.16×10 ^-8 .

Intracellular increases in calcium were reported using max-min statistics (baseline at rest was subtracted from the peak resulting from addition of the stimulating antibody using Molecular Devices FLIPR Control and Statistical Export software). _IC50 was determined using nonlinear curve fitting (GraphPad Prism software). Representative results are in Table 1.

The measurement results

The compounds used in the present invention can be formulated as pharmaceuticals with a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. Among other routes of administration, the compounds used herein are effective when administered by other routes of administration including continuous (intravenous infusion) topical parenteral, intramuscular, intravenous and suppository administration. The preferred mode of administration is generally oral using a conventional oral dosage regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

Compounds useful as medicines for BTK and SYK-mediated diseases, and their pharmaceutically acceptable salts, and one or more common excipients, carriers or diluents can be placed in the form of pharmaceutical compositions and unit dosages . Pharmaceutical compositions and unit dosage forms may contain the usual ingredients in conventional proportions with or without additional active compounds or ingredients, and may contain the daily dosage ranges contemplated for use. equivalent to any suitable effective amount of the active ingredient. The pharmaceutical composition can be used for oral application in the form of solids such as tablets or filled capsules, semi-solids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules; or for rectal administration. or in the form of suppositories for vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or active compounds (w/w). The term "formulation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and those skilled in the art understand that the active ingredient may be present in different formulations depending on the target organ or tissue and depending on the desired dosage and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound used in the preparation of a pharmaceutical composition that is generally safe, non-toxic and has no biological activity or side effects, and includes excipients that are useful for veterinary use as well as human pharmaceutical applications. The compounds disclosed herein can be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

The "pharmaceutically acceptable salt" form of an active ingredient may also initially confer on the active ingredient desired pharmacokinetic properties which are lacking in the non-salt form and may even positively influence the pharmacokinetics of the active ingredient with respect to its therapeutic activity in vivo. The phrase "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Said salts include: (1) acid addition salts, formed with inorganic acids such as HCl, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as HOAc, propionic acid, hexanoic acid, cyclopentanepropionic acid, Glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid Acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethyl HOAc, tert-butyl HOAc , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) when the acid protons present in the parent compound are replaced by metal ions such as alkali metal ions , salts formed when alkaline earth ions or aluminum ions are replaced; or salts formed by coordination with organic bases such as EtOH amine, di-EtOH amine, tri-EtOH amine, tromethamine, N-methylglucamine, etc. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt as defined herein.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient usually is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, astragalus, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa Grease etc. Solid form preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like in addition to the active ingredient.

Liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions, are also suitable for oral administration. These include solid form preparations, which can be converted, immediately before use, to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, such as phosphatidylcholine, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending ingredients.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection such as bolus injection, or continuous infusion) and may be presented in unit dosage form such as ampoules, prefilled syringes, small volume infusion solutions, or multidose containers with added preservatives are present. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and may contain formulating agents such as preservatives , wetting agent, emulsifying or suspending agent, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, which is mixed with a suitable excipient, e.g. sterile, apyrogenic, before use. The original water is reconstituted.

The pharmaceutical formulations disclosed herein may be administered as suppositories. A low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously, for example by stirring. Next, the molten homogeneous mixture is poured into conventional sieving molds, allowed to cool and solidify.

The drugs disclosed herein can be used for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays contain in addition to the active ingredient such carriers as are known in the art to be suitable.

酮(1-十二烷基氮杂-环庚-2-酮)组合。将持续释放递送系统通过外科手术或注射皮下插入皮下层。皮下植入物在脂溶性膜中包封化合物，所述膜例如硅橡胶或可生物降解的聚合物例如聚乳酸。Formulations can be prepared, when desired, with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the drugs disclosed herein can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is desired and when patient compliance with the treatment regimen is important. Compounds in transdermal delivery systems are often bound to a skin-adhesive solid support. Compounds of interest can also be combined with penetration enhancers such as lauryl nitrogen

Ketone (1-Dodecylazepine-Cycloheptan-2-one) combination. The sustained release delivery system is inserted subcutaneously into the subcutaneous layer either surgically or by injection. Subcutaneous implants encapsulate the compound in a fat-soluble membrane such as silicone rubber or a biodegradable polymer such as polylactic acid.

Suitable formulations, as well as pharmaceutical carriers, diluents and excipient. An experienced formulation scientist can modify formulations based on the teachings of the present invention to provide multiple formulations for specific routes of administration without destabilizing the drugs disclosed herein or compromising their therapeutic activity.

Modification of the drugs disclosed herein to increase their solubility in water or other excipients, for example, can readily be achieved by minor modifications (salt formation, esterification, etc.), which are within the purview of one of ordinary skill in the art . It is also known to those skilled in the art to vary the route of administration and dosage regimen of a particular compound so that the pharmacokinetics of the compounds of the invention maximize beneficial effects in patients.

As used herein, the term "therapeutically effective amount" refers to the amount required to alleviate the symptoms of a disease in an individual. The dosage can be adjusted to the individual requirements in each particular case. The dosage can vary widely depending on factors such as the severity of the disease being treated, the age and general health of the patient, other drugs treating the patient, the route and form of administration, and the Practitioner's preference and experience. For oral administration, a daily dosage in the range of about 0.01 and about 1000 mg/kg body weight/day should be suitable in monotherapy and/or combination therapy situations. Preferred daily dosages are in the range of about 0.1 and about 500 mg/kg body weight/day, more preferably in the range of 0.1 and about 100 mg/kg body weight/day, most preferably in the range of 1.0 and about 10 mg/kg body weight/day. Thus, for administration to a 70 kg human, the dosage range is about 7 mg to 0.7 g/day. The daily dose can be administered in a single dose or in divided doses, typically 1-5 doses/day. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Subsequently, the dosage is increased by small increments until the optimum effect for the individual patient is reached. Those skilled in the art of treating the diseases described herein will be able to determine, without undue experimentation and based on personal knowledge, experience and the disclosure of this application, a therapeutically effective amount of a compound of the invention for a given disease and patient.

Example

General experiment for the synthesis of 2,3-phthalazinone derivatives:

Method A

Example A-1: 4-(5-methyl-2H-pyrazol-3-ylamino)-phenyl-2H-2,3-naphthyridine-1-one.

2-Phenyl-2,3-dihydro-2,3-naphthyridine-1,4-dione : Phenylhydrazine (59.4 g, 0.55 mol) was added in one portion in HOAc ( 500ml) in a stirred mixture of phthalic anhydride (74.0g, 0.5mmol). The reaction mixture was heated to 125°C for 2 hours, then allowed to cool to room temperature. The resulting suspension was poured into water (500ml) and the solid was isolated by filtration. Next, the solid was stirred in 1M _Na2CO3 ( _400ml ), and the remaining undissolved solid was removed by filtration. _The solid was washed two more times with two 400ml portions of 1M _Na2CO3 .

The basic solutions were combined and acidified by the dropwise addition of concentrated HCl until gas evolution ceased. The formed precipitate was isolated by filtration and dried in a vacuum oven (50° C.) for 18 hours to give phthalazinone (46.3 g, 39% yield) as a white solid. ¹ H-NMR: (400MHz; D ₆ -DMSO); 11.7(1H,br.s), 8.30(1H,d), 8.03(1H,d), 7.93(2H,m), 7.67(1H,d) , 7.51(1H, t), 7.4(1H, t); MS(ESI ⁺ )=(M+H) ⁺²³⁹

4-Bromo-2-phenyl-2H-2,3-phthalazin-1-one (brominated) : Phosphorus oxybromide (3.13g, 10.9mmol) was added in 1,2DCE (15.0ml) in a stirred suspension of 2-phenyl-2,3-dihydro-2,3-naphthyridine-1,4-dione (1.30 g, 5.4 mmol). The reaction was heated to 100°C for 18 hours, then cooled and poured into water.

The aqueous layer was made basic with 1M _Na2CO3 and extracted into DCM (3 x 100ml) _. The organic layers were combined, dried ( _MgSO4 ) and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc: hexanes) to afford bromophthalazinone as a white solid (0.770 g, 2.6 mmol, 48% yield). ¹ H-NMR: (400MHz; D ₆ -DMSO); 8.20(1H,dd), 7.91(1H,td), 7.89(1H,td), 7.35-7.55(5H,m); MS(ESI ⁺ )= (M+H) ⁺ 301, 303

4-(5-Methyl-2H-pyrazol-3-ylamino)-phenyl-2H-2,3-phthalazin-1-one (A-1) ( typical procedure for Buchwald reaction): 4-Bromo-2-phenyl-2H-2,3-phthalazin-1-one (0.750 g, 2.5 mmol ), sodium tert-butoxide (0.337g, 3.5mmol), 3-amino-5-methylpyrazole (0.291g, 3mmol), tris-(dibenzylideneacetone)-dipalladium (0.115g, 0.125mmol) and 2-(di-tert-butylphosphine)-biphenyl (0.075 g, 0.25 mmol). The reaction mixture was heated to 100 °C for 20 hours with stirring, then cooled to room temperature. Diethyl ether (10 ml) was added and the precipitated solid was filtered to give the crude product as a gray solid (0.6 g, 76% yield). A 0.06 g portion of the crude product was triturated with MeCN (2 ml) and water (2 ml) to give the title compound (0.045 g, 58% yield based on recovered material). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.96 (1H, s), 9.33 (1H, s), 8.53 (1H, d), 8.38 (1H, d), 7.92-7.99 (2H, m), 7.88 (2H, d), 7.77 (2H, t) 7.34 (1H, t) 6.24 (1H, s) 2.18 (3H, s) MS (ESI ⁺ ) = (M + H) ⁺ 318.29.

Using the experimental conditions described above (Method A) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) A-2 2-Benzyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.86(1H, s), 9.25(1H, s), 8.46(1H, d), 8.32(1H, d), 7.84-.7.94(2H, m), 7.25-7.38( 5H m), 6.10 (1H, s), 5.24 (2H, s) 2.17 (3H, s) 332.08 A-3 2-Methyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.70(1H, s), 9.00(1H, s), 8.23(1H, d), 8.10(1H d), 7.73-7.64(2H, m), 6.13(1H, S) , 3.44(3H S), 2.04(3H, s) 389.27 A-4 2-isobutyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.76(1H, s), 9.00(1H, s), 8.2(1H, d), 8.15(1H d), 7.77-7.67(2H, m), 6.17(1H, S) , 3.71(2H d), 2.10-2.07(4H, m), 0.75(6H, d) 298.33 A-5 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(2,2,2- (400MHz, D ₆ -DMSO) 9.58(1H, s), 8.47(1H, d), 8.34(1H, 323.10

Trifluoro-ethyl)-2H-2,3-naphthyridine-1-one d), 8.01-7.83(2H m), 6.34(1H, S), 4.93(2H q), 2.25(3H, s) A-6 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-p-tolyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.70(1H s), 9.04(1H, s), 8.26(1H, d), 8.11(1H, d), 7.74-7.64(2Hm), 7.34(2H, d), 7.05 (2H d), 6.01 (1H, s), 2.14 (3H, s), 1.94 (3H, s) 332.34 A-7 2-(4-fluoro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 12.17(1H s), 9.51(1H, s), 8.73(1H, d), 8.59(1H, d), 8.20-8.10(2Hm), 7.99-7.95(2H, m) , 7.55(2H t), 6.45(1H, s), 2.40(3H, s) 336.31 A-8 2-(4-tert-butyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.36(1H, s), 8.46(1H, d), 8.38(1H, d), 8.00-7.89(2H m), 7.62(2H, d), 7.50(2H, d) 6.24(1H,s), 2.21(3H,s), 1.34(9H,s) 374.40 A-9 2-(4-methoxy-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.72(1H,s) 9.05(1H,s), 8.28(1H,d), 8.15(1H,d), 7.76-7.66(2Hm), 7.40(2H,d), 6.84 (2H, d) 6.03 (1H, s), 3.61 (3H, s), 1.97 (3H, s) 348.34 A-10 4-(1H-pyrazol-3-ylamino)-2-p-tolyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 12.05(1H,s) 9.22(1H,s), 8.33(1H,d), 8.15(1H,d), 7.78-7.68(2Hm), 7.39-7.37(3H,m) , 7.09(2H, d) 6.29(1H, s), 2.16(3H, 318.32

s) A-11 2-(4-methoxy-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.91(1H,s), 9.28(1H,s), 8.47(1H,d), 8.36(1H,d), 7.97-7.89(2H,m), 7.37(2H,d ), 6.18(1H,d), 5.21(2H,s), 3.76(3H,s), 2.24(3H,s) 362.36 A-12 2-(3-methoxy-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.88(1H, s), 9.23(1H, s), 8.44(1H, d), 8.32(1H, d), 7.92-7.86(2H, m), 7.24(1H, t ), 6.96(1H,d), 6.93(1H,s), 6.84(1H,s), 6.15(1H,s), 5.21(2H,s), 3.72(3H,s), 2.18(3H,s) 362.35 A-13 2-(2,5-Difluoro-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.88(1H, s), 9.25(1H, s), 8.32(1H, d), 7.93-7.85(2H, m), 7.32-7.21(3H, m), 5.93(1H ,s), 5.29(2H,s), 2.16(3H,s) 368.14 A-14 2-(4-Methanesulfonyl-benzyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.20(1H, s), 8.35(1H, d), 8.25(1H, d), 7.89-7.79(4H, m), 7.53(2H, d), 6.00(1H, s ), 5.30(2H, s), 3.08(3H, s), 2.12(3H, s) 410.12 A-15 2-(3,4-Difluoro-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, _D6 -DMSO) 9.51(1H, s), 8.34(1H, s), 8.24(1H, d), 7.91-7.80(2H, m), 7.41-7.29(2H, m), 7.16-7.13 (1H, m), 6.04 (1H, s), 5.21 (2H, s), 2.16 (3H, s) 368.20

A-16 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(2-methyl-thiazol-4-ylmethyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO)9.82(1H,s), 8.39(1H,d), 8.33(1H,d), 7.99-7.88(2H,m), 7.36(1H,s), 6.16(1H,s ), 5.34(2H, s), 2.64(3H, s), 2.26(3H, s) 353.18 A-17 4-(5-Methyl-2H-pyrazol-3-ylamino)-2-pyridin-4-ylmethyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO)9.38(1H,s), 8.70(2H,d), 8.44(1H,d), 8.31(1H,d), 7.98-7.86(2H,m), 7.69(2H,d ), 6.06(1H, s), 5.46(2H, s), 2.17(3H, s) 333.21 A-18 4-(5-Methyl-2H-pyrazol-3-ylamino)-2-pyridin-3-ylmethyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.38(1H,s), 8.68(2H,d), 8.54(2H,d), 8.29(2H,d), 8.17(2H,dd), 8.05(2H,d), 7.83-7.72 (4H, m), 7.58 (2H, dd), 5.95 (2H, s), 5.27 (3H, s), 2.07 (4H, s) 333.14 A-19 2-(2-fluoro-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, _D6 -DMSO) 9.45(1H, s), 8.42(1H, d), 8.31(1H, dd), 7.96-7.85(2H, m), 7.38-7.31(2H, m), 7.24-7.13 (2H, m), 5.97 (1H, s), 5.33 (2H, s), 2.16 (3H, s) 350.11 A-20 2-(4-fluoro-benzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.53(1H, s), 8.40(1H, d), 8.31(1H, dd), 7.96-7.85(2H, m), 7.41(2H, dd), 7.15(2H, t ), 6.11(1H, s), 5.26(2H, s), 2.22(3H, s) 350.11 A-21 2-(3,5-difluoro-benzyl)-4-(5-methyl-1H-pyridine (400MHz, D ₆ -DMSO) 9.59(1H, s), 8.44(1H, d), 8.33(1H, 368.10

Azol-3-ylamino)-2H-2,3-naphthyridine-1-one dd), 7.99-7.88(2H, m), 7.17(2H, tt), 7.08(2H, dd), 6.12(1H, s), 5.32(2H, s), 2.23(3H, s) A-22 4-(5-Methyl-2H-pyrazol-3-ylamino)-2-pyridin-2-ylmethyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.23(1H, s), 8.54(1H, d), 8.47(1H, d), 8.31(1H, d), 7.97-7.85(2H, m), 7.76(1H, t ), 7.32-7.24 (2H, m), 5.95 (1H, s), 5.36 (2H, s), 2.13 (3H, s) 333.28 A-23 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.73(1H, br s), 8.99(1H, br s), 8.25(1H, d), 8.10(1H, d), 7.71-7.62(2H, m), 6.16(1H , t), 5.10-5.03 (1H, m), 2.05 (3H, s), 1.13 (6H, d) 284.34 A-24 3-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-ylmethyl]-benzoic acid (400MHz, D ₆ -DMSO) 11.94-11.76 (1H, m), 9.26 (1H, br s), 8.46 (1H, d), 8.31 (1H, d), 7.92-7.82 (3H, m), 7.75 ( 1H, d), 7.33-7.22 (2H, m), 6.08 (1H, s), 5.23 (2H, s), 2.14 (3H, s) 376.15 A-25 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-trifluoromethyl-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 9.28(1H, s), 8.41(1H, d), 8.27(1H, d), 7.96-7.73(6H, m), 6.13(1H, s), 2.05(3H, s) 386,1

According to Method E, Example A-2 was synthesized as in Example E-1.

Method B :

Example B-1: 2-(4-chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one

2-(4-Chlorophenyl)-2,3-dihydro-2,3-naphthyridine-1,4-dione : At room temperature, 4-chlorophenylhydrazine hydrochloride (5.00g , 28 mmol) was added in one portion to a stirred mixture of phthalic anhydride (3.70 g, 25 mmol) in HOAc (50 ml). The mixture was heated to 125°C for 2 hours and then allowed to cool to room temperature. The suspension was poured into water (100ml) and the precipitate was filtered. The precipitate was stirred in 1M _Na2CO3 (100ml) and the remaining undissolved solids were removed by _filtration . The solid _was washed with another 100ml portion of 1M _Na2CO3 .

The basic aqueous solutions were combined and acidified by the dropwise addition of concentrated HCl until gas evolution ceased. A white precipitate formed and was filtered and dried in a vacuum oven (50 °C) for 18 hours to give the naphthyridine (270 mg, 4% yield). The solid _, insoluble in 1M _Na2CO3 , was stirred in glycerol (50ml) and heated to 150°C for 10 hours. Next, the reaction mixture was diluted with water (50 ml). 4M HCl was added dropwise until a precipitate formed. It was filtered, resuspended in MeOH (30ml) and isolated by filtration. The product was dried under vacuum to afford the desired naphthyridine (3.6 g, 72% yield). ¹ H-NMR: (400MHz; D ₆ -DMSO); 12.1 (1H, br.s), 8.3 (1H, d), 7.9-8.0 (3H, m), 7.7 (2H, d), 7.6 (2H, d); MS(ESI ⁺ )=(M+H) ^+273,275

Next, this material was brominated with phosphorus oxybromide and used in a Buch-wald reaction as described in Method A to give the corresponding 2-(4-chloro-phenyl)-4-(5-methyl- 1H-pyrazol-3-ylamino)-2H-2,3-phthalazin-1-one (Example B-1).

Using the experimental conditions reported above (Method B) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) B-1 2-(4-Chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 11.97(1H,s), 9.34(1H,s), 8.51(1H,d), 8.38(1H,d), 7.99-7.89(2Hm), 7.80(2H,d), 7.58 (2H, d) 352.30

6.24(1H, s), 2.20(3H, s) B-2 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-m-tolyl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.45(1H s), 8.49(1H, d), 8.38(1H, d), 7.98-7.91(2H, m), 7.54-7.50(1H m), 7.38(1H, t ), 7.17(1H d), 6.26(1H, s), 2.38(3H, s), 2.20(3H, s) 332.34 B-3 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-nitro-benzyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.32(1H, s), 8.34(2H, d), 8.21(2H, d), 8.0(2H, d), 7.49-.7.85(2H, m), 7.49(2H d ), 5.93(1H, s), 5.29(2H, s), 2.04(3H, s) 377.24

Method C

Example C-1: 2-(4-aminobenzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one

Tin(II) chloride dihydrate (1.3 g, 5.76 mmol) was added to 4-(5-methyl-1H-pyrazol-3-ylamino)-2-(4-nitro-benzyl)- 2H-2,3-Naphthyridine-1-one (Example B-3) (600 mg, 1.6 mmol) in suspension in dimethylformamide (DMF) (10 ml). The reaction mixture was stirred overnight at room temperature. DMF was evaporated under reduced pressure and the residue was dissolved in DCM. A saturated solution of potassium sodium tartrate tetrahydrate in water (20ml) was added and the mixture was stirred for 30 minutes.

The phases were separated and the aqueous phase was back extracted with DCM (20ml). The organic layers were combined, washed with brine and evaporated under reduced pressure to give 2-(4-aminobenzyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H- as an off-white solid 2,3-Naphthyridine-1-one (55 mg, 10% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.37 (1H, s), 8.40 (2H, d), 8.28 (2H, d), 7.81-7.91 (2H, m), 7.32 (2H, d), 7.04 (2H d), 6.12 (1H, s), 5.18 (2H, s), 2.17 (3H, s), MS (ESI ⁺ ) = (M + H) ⁺ 347.31.

Using the experimental conditions reported above (Method C) and suitable starting materials W-3, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) C-2 2-(4-amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 11.90(1H, s), 9.15(1H, s), 8.47(1H, d), 8.33(1H, d), 7.85-7.94(2H, m), 7.28(2H, d), 6.65(2H, d), 6.25(1H, s), 5.23(2H, s), 2.18(3H, s) 333.3

Method D

Example D-1: N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl Methyl]-phenyl}-acetamide

4-Bromo-2-(4-aminobenzyl)-2H-2,3-phthalazin-1-one : Add tin(II) chloride dihydrate (68mg, 3.6eq) to 4-bromo A suspension of 2-(4-nitrobenzyl)-2H-2,3-naphthyridine-1-one (30 mg, 0.09 mmol) in DMF (0.5 ml). The reaction mixture was stirred overnight at room temperature. DMF was evaporated under reduced pressure and the residue was dissolved in DCM (0.5ml). A saturated solution of potassium sodium tartrate tetrahydrate in water (0.5 ml) was added and the mixture was stirred for 30 minutes.

The phases were separated and the aqueous phase was back extracted with DCM (0.5ml). The organic layers were combined, washed with brine and evaporated under reduced pressure to give the desired product as an off-white solid (23 mg, 87% yield) ¹ H-NMR: (400 MHz; C ₆ D ₆ ); 8.42 (1H, d) , 7.91 (1H, d), 7.83 (2H, m), 7.33 (2H, d), 6.63 (2H, d), 5.25 (2H, s). MS (ESI ⁺ ) = (M + H) ⁺ 330.2, 332.2.

4-Bromo-2-(4-acetylaminobenzyl)-2H-2,3-naphthyridine-1-one : add acetic anhydride (0.43ml, 4.5mmol) to 4-bromo-2- In a mixture of (4-aminobenzyl)-2H-2,3-phthalazin-1-one (500mg, 1.5mmol) and pyridine (0.49ml, 6mmol) in MeCN (5ml). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure. 1M aqueous ammonia in MeOH (2ml) was added and the reaction mixture was stirred for 1 hour. Solvent was removed under reduced pressure. The residue was triturated with DCM to give the product as an off-white solid (398 mg, 71% yield) MS (ESI ⁺ ) = (M+H) ⁺ 372.2, 374.2.

This material was then used in the Buchwald reaction as described in Method A to give the corresponding N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo- 1H-2,3-Naphthalene-2-ylmethyl]-phenyl}-acetamide (Example D-1).

Using the experimental conditions reported above (Method D) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) D-1 N-{4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-ylmethyl]-phenyl }-Acetamide (400MHz, D ₆ -DMSO) 9.94(1H, s), 9.26(1H, s), 8.42(2H, d), 8.32(2H d), 7.85-7.94(2H, m), 7.52(2H, d) , 7.31(2H d), 6.10(1H, s), 5.18(2H, s), 2.19(3H, s), 2.17(3H, s) 389.27 D-2 N-{4-[1-oxo-4-(1H-pyrazol-3-ylamino)-1H-2,3-naphthyridine-2-ylmethyl]-phenyl}-acetamide (400MHz, D ₆ -DMSO) 12.16(1H,s) 9.84(1H,s), 8.38(1H,d), 8.25(1H,d), 7.87-7.78(2Hm), 7.50(1H,d), 7.45 (2H, d) 7.23 (2H, d), 6.40 (1H, s), 5.10 (2H, s), 1.93 (3H, s) 375.29

Method E

Example E-1: 2-Benzyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one

4-Bromo-2H-2,3-naphthyridine-1-one : Suspend 2,3-dihydro-1,4-naphthyridine (12.5 g, 78 mmol) in DCE (200 ml) and phosphorus pentabromide (50.0 g, 116 mmol) was added in one portion and the reaction was heated to reflux for 24 hours. Another portion of phosphorus pentabromide (20.0 g, 70 mol) was added and the reaction was heated for an additional 24 hours. The reaction was cooled to room temperature and poured into ice water. The resulting precipitate was filtered and washed with water to give a crude mixture of mono and dibrominated products (22.8 g).

The crude material was suspended in HOAc (230.0 mL) and heated to 120 °C for 2 hours. The reaction was cooled to room temperature and poured into ice water and the resulting precipitate was filtered. The solid was washed with water and dried to give the title compound (10.4 g, 60% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 12.95(1H, s), 8.25(1H, dd), 8.03(1H, ddd), 7.96-7.90-(2H, m); MS(ESI ⁺ ) ＝(M+H) ⁺ 225 & 227

2-Benzyl-4-bromo-2H-2,3-naphthyridine-1-one : 4-bromo-2H-2,3-naphthyridine-1-one (10.38g, 46mmol ) was dissolved in dimethylformamide (DMF) (60ml). To this was added NaH (60%, 1.55 g, 46.2 mmol) as a DMF suspension (20 ml). The mixture was stirred at room temperature for 30 minutes, then a portion of benzyl bromide (13.82 g, 50.8 mmol) was added as a solution in DMF (20 ml). The reaction mixture was stirred for 2 hours, then DMF was removed under reduced pressure and the resulting crude material was purified by column chromatography (gradient elution: 100% heptane to 20% EtOAc:heptane) to afford the title compound (8.16 g , 56% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 8.30 (1H, dd), 8.03 (1H, ddd), 7.97-7.91 (2H, m), 7.34-7.27 (5H, m), 5.31 (2H, s); MS(ESI ⁺ ) = (M+H) ⁺ 315 & 317

This material was then used in the Buchwald reaction, as described in Method A, to give the corresponding 2-benzyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one (Example E-1).

Using the experimental conditions reported above (Method E) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) E-1 2-Benzyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.86(1H, s), 9.25(1H, s), 8.46(1H, d), 8.32(1H, d), 7.84-.7.94(2H, m), 7.25-7.38( 5H m), 6.10 (1H, s), 5.24 (2H, s) 2.17 (3H, s) 332.08 E-2 7-Fluoro-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diaze (400MHz, D ₆ -DMSO) 9.35(1H, s), 8.53(1H, dd), 7.95(1H, dd), 7.82(1H, ddd), 6.35(1H, s), 5.27-5.19(1H, m ), 2.26(3H,s), 302.29

Xinaphthin-1-one 1.32(6H, s) E-3 6-Fluoro-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.09(1H, s), 8.19-8.14(2H, m), 7.56-7.50(1H, m), 6.18(1H, s), 5.09-5.00(1H, m), 2.07 (3H, s), 1.14 (6H, d) 302.29 E-4 2-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3- Naphthalene-1-one (400MHz, D ₆ -DMSO)9.43(1H,s), 8.40(1H,d), 8.22(1H,d), 8.00(2H,d), 7.93-7.81(2H,m), 7.04(2H,d ), 6.12(1H, s), 5.54(2H, s), 3.80(3H, s), 2.11(3H, s) 390.14 E-5 2-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3- Naphthalene-1-one (400MHz, D ₆ -DMSO) 9.38(1H,s), 8.43(1H,d), 8.21(1H,d), 7.92-7.80(2H,m), 7.61(1H,d), 7.49-7.42(2H , m), 7.21 (1H, d), 6.11 (1H, s), 5.57 (2H, s), 3.77 (3H, s), 2.09 (3H, s) 390.15 E-6 4-(5-methyl-1H-pyrazol-3-ylamino)-2-[2-oxo-2-(4-trifluoromethoxy-phenyl)-ethyl]-2H-2, 3-Naphthyridine-1-one (400MHz, D ₆ -DMSO) 12.06 (1H, br s), 9.41 (1H, br s), 8.64 (1H, d), 8.45-8.36 (3H, m), 8.14-8.02 (2H, m), 7.75 (2H, d), 6.38 (1H, s), 5.79 (2H, s), 2.30 (3H, s) 444.23 E-7 2-(2-Benzo[1,3]dioxol-5-yl-2-oxo-ethyl)-4-(5-methyl-1H-pyrazol-3-ylamino (400MHz, D ₆ -DMSO) 9.26(1H, br s), 8.48(1H, d), 8.30(1H, d), 7.97-7.88(2H, m), 7.75(1H, d), 7.56(1H, s), 7.12 (1H, d), 6.18 (2H, s), 5.55 (2H, s), 2.16 (3H, s) 404.18

Base)-2H-2,3-naphthyridine-1-one E-8 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-2H-2,3 -Naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.84 (1H, br s), 9.26 (1H, br s), 8.42 (1H, d), 8.22-8.20 (3H, m), 7.91-7.80 (4H, m), 6.12 (1H, s), 5.61 (2H, s), 2.08 (3H, s) 428.09 E-9 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(2-oxo-2-phenyl-ethyl)-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 11.91(1H, brs), 9.31(1H, brs), 8.48(1H, d), 8.30(1H, d), 8.09(2H, d), 7.98-7.87(2H, m), 7.74-7.70 (1H, m), 7.62-7.58 (2H, m), 6.21 (1H, s), 5.63 (2H, s), 2.15 (3H, s) 360.10 E-10 2-allyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.90(1H, s), 9.20(1H, s), 8.45(1H, d,), 8.29(1H, d), 7.98-7.81(2H, m), 6.36(1H, s), 6.06-5.94(1H, m), 5.23-5.15(2H, m), 4.69-4.61(2H, m), 2.21(3H, s) 282.09 E-11 2-Cyclopropylmethyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.91(1H,s), 9.16(1H,s), 8.44(1H,d), 8.29(1H,dd), 7.94-7.82(2H,m), 6.36(1H,s ), 3.91(2H, d), 2.23(3H, s), 1.34-1.25(1H, m), 0.52-0.46(2H, m), 0.43-0.37(2H, m) Tr=1.54min, m/z (ES ⁺ )(M+H) ⁺ 296.12 E-12 4-(5-Methyl-1H-pyridine (400MHz, D ₆ -DMSO) 11.88(1

Azol-3-ylamino)-2-(4-methylthio-benzyl)-2H-2,3-naphthyridine-1-one H, s), 9.21 (1H, s), 8.44 (1H, d), 8.31 (1H, dd), 7.94-7.84 (2H, m), 7.34-7.30 (2H, m), 7.25-7.21 (2H, m), 6.11(1H, s), 5.19(2H, s), 2.43(3H, s), 2.19(3H, s) Tr=1.87min, m/z(ES ⁺ )(M+H) ⁺ 378.08

Example E-13: 2-(2-Hydroxy-2-phenyl-ethyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine Naphthalene-1-one.

Sodium borohydride (6 mg, 0.15 mmol) was added in one portion to 4-(5-methyl-1H-pyrazol-3-ylamino)-2-(2-oxo-2-phenyl-ethyl)- A stirred solution of 2H-2,3-phthalazin-1-one (17 mg, 0.05 mmol) (Example E-9) in THF (1 ml). The reaction mixture was stirred at room temperature for 2 hours. After this time, LC-MS showed complete consumption of starting material, MeOH (0.5ml) was added and the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography (elution: 97% DCM, 3% MeOH) to give the title compound (2.2 mg, 12% yield) as a white solid. MS (ESI ⁺ ) = (M + H) ⁺ 361.98.

Method F:

Example F-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-morpholino-2H-2,3-naphthyridine-1- ketone

7-Nitro-2,3-dihydro-2,3-naphthyridine-1,4-dione : At room temperature, hydrazine hydrate (26.6 g, 0.53 mol) was added in one portion to 4-nitro In a stirred mixture of phthalic anhydride (100 g, 0.52 mol) in HOAc (1.0 L). The mixture was heated to 120°C for 2 hours and then allowed to cool to room temperature. The solid was filtered, washed with water (250ml) and dried in a vacuum oven at 50°C for 20 hours to give the nitronaphthyridine (95g, 88% yield). MS(ESI ⁺ )＝(M+H ⁺ )208.

7-nitro-4-bromo-2H-2,3-naphthyridine-1-one : 7-nitro-2,3-dihydro-2,3-naphthyridine-1,4 - Diketone (95.0 g, 0.46 mol) was suspended in DCE (1.0 L) and phosphorus pentabromide (789.0 g, 1.83 mol) was added in three portions and the reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured onto ice (2.5 kg), the resulting precipitate was filtered and washed with water to give the crude product (160 g).

The crude material was suspended in HOAc (1.60 L) and heated to 125 °C for 2 hours. The reaction was cooled to room temperature and poured onto ice (1.5 kg) and the resulting precipitate was filtered. The solid was washed with water and dried to give the title compound (84 g, 68% yield) as a yellow solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 13.29 (1H,), 8.83 (1H, d), 8.79 (1H, dd), 8.61 (1H, dd), 8.54 (1H, d), 8.46 ( 1H, d), 8.16(d) MS(ESI ⁺ ) = (M+H) ⁺ 269 & 271

7-nitro-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one : 7-nitro-4-bromo-2H-2,3-diazepine Xinaphthin-1-one (84 g, 0.31 mol) was dissolved in dimethylformamide (DMF) (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at room temperature for 30 minutes, then 2-bromo-propanol (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours, LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g 0.15 mol) and the reaction was stirred for a further 24 hours. DMF was removed under vacuum and the resulting crude material was purified by continuous column chromatography (elution: 92% heptane to 8% EtOAc) to give the title compound (38.8 g, 40% yield) as a pale yellow solid. ¹ H-NMR: (400 MHz, D ₆ -DMSO), 8.88 (1H, d), 8.87 (1H, dd), 8.16 (1H, d), 5.19 (1H, m), 1.13 (6H, d).

7-Amino-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one : 7-nitro-2-isopropyl-4-bromo-2H-2 , 3-Naphthyridine-1-one (4.6 g, 0.015 mol) was dissolved in a 5:1 mixture of EtOH and water (150 ml). To this solution were added iron powder (2.14 g, 0.039 mol) and concentrated HCl (1 ml), and the mixture was heated to 80° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, which was washed with EtOH (100 ml), and the solution was concentrated under vacuum to give the title compound (4.2 g, 98% yield ), which is a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 7.56(1H,d), 7.28(1H,s), 7.13(1H,d), 6.47(2H,s), 5.24-5.09(1H,m) , 1.23(6H, d); MS(ESI ⁺ )=(M+H) ^+282,284

7-morpholino-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one : to 7-amino-2-isopropyl-4-bromo-2H- To a solution of 2,3-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml) was added potassium carbonate (2 g, 0.014 mol). After 5 minutes, bis(2-chloroethyl)ether (0.41 g, 0.0028 mol) was added and the solution was heated to 140°C for 24 hours. Subsequently, LC-MS showed complete consumption of starting material and the mixture was cooled, concentrated in vacuo and purified by flash column chromatography (elution: 70% heptane, 30% EtOAc) to give the title compound (0.2 g, 20 % yield) as a white solid.

This material was then used in the Buchwald reaction, as described for Method A, to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-mol Lino-2H-2,3-phthalazin-1-one (Example F-1).

Using the experimental conditions reported above (Method F) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) F-1 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-morpholino-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.86(1H,s), 8.97(1H,s), 8.29(1H,d), 7.57(1H,d), 7.52(1H,d), 6.35(1H,brs), 5.28-5.20 (1H, m), 3.79-3.74 (4H, m), 3.21 (4H, blurred), 2.23 (3H, s), 1.30 (6H, d) 368.15 F-2 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-6-morpholino-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.88(1H,s), 9.19(1H,s), 8.07(1H,d), 7.65(1H,s), 7.41(1H,dd), 6.37(1H,s), 5.25-5.16(1H,m), 3.80-3.73(4H,m), 3.44-3.35(4H,m), 1.28(6H,d) 369.37 F-3 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-8-morpholino-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 9.45(1H, brs), 8.35(1H, brs), 8.03(1H, brs), 6.33(1H, s), 5.31-5.17(1H, m), 3.96(4H, brs ), 3.51 (4H, br s), 2.26 (3H, s), 1.35 (6H, d) 369.30 F-4 2-Benzyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-morpholino-2H-2,3-diazepine (400MHz, D ₆ -DMSO)9.50(1H,s), 8.10(1H,d), 7.61(1H,d), 7.46(1H,dd), 7.34-7.23(5H,m), 6.14(1H,s ), 5.22(2H,s), 3.83-3.72 417.30

Naphthalene-1-one (4H, m), 3.42-3.40 (4H, m), 2.20 (3H, s) F-5 2-isopropyl-7-(4-methyl-piperazin-1-yl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-diazepine Naphthalene-1-one (400MHz, CDCl ₃ ) 7.83(1H,d), 7.61(1H,d), 7.31(1H,dd), 7.15(1H,s), 6.33(1H,s), 5.49-5.41(1H,m), 3.46-3.41(4H,m), 2.61-2.55(4H,m), 2.37(3H,s), 2.35(3H,s), 1.43(6H,d) 382.33 F-6 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-dimethylamino-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.21(1H, s), 8.27(1H, d), 7.41(1H, d), 7.35(1H, dd), 6.42(1H, s), 5.36-5.29(1H, m ), 3.16(6H, s), 2.34(3H, s), 1.39(6H, d) 327.36 F-7 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-6-dimethylamino-2H-2,3-naphthyridine-1-one 327.30 F-8 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-8-dimethylamino-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.82 (1H, br s), 8.77 (1H, br s), 7.67-7.56 (2H, m), 7.20 (1H, d), 6.26 (1H, br s), 5.26- 5.15(1H,m), 2.84(6H,s), 2.22(3H,s), 1.27(6H,d) 327.18 F-9 4-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-7-dimethylamino-2-isopropyl-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 11.89(1H, brs), 8.90(1H, brs), 8.23(1H, brs), 7.32(1H, d), 7.24(1H, d), 6.25(1H, brs), 5.29-5.18(1H,m), 3.07(6H,s), 1.92-1.84(1H,m), 1.29(6H,d), 0.98-0.88(2H,m), 0.65(2H,dd) 353.41

F-10 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-piperidin-1-yl-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 9.04(1H, s), 8.32(1H, d), 7.63(1H, d), 7.57(1H, dd), 6.42(1H, s), 5.40-5.25(1H, m), 3.49 (4H, s), 2.32 (3H, s), 1.70 (6H, br s), 1.39 (6H, d) 367.22 F-11 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-pyrrolidin-1-yl-2H-2,3-naphthyridine-1-one (250MHz, DMSO) 8.88(1H, s), 8.23(1H, d), 7.18(1H, d), 7.11-7.03(1H, m), 6.35(1H, s), 5.33-5.18(1H, m) , 3.39(4H, brs), 2.24(3H, s), 2.02(4H, brs), 1.31(6H, d) 353.18

Method G:

Example G-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-2H-2,3-naphthyridine-1- ketone

7-Hydroxy-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one : Slowly add concentrated sulfuric acid (17ml) to 7-amino-2-isopropyl-4- Bromo-2H-2,3-phthalazin-1-one (4.6 g, 0.016 mol) in a solution of HOAc (50 ml). The reaction mixture was cooled to 0 °C and a solution of _NaNO2 (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 minutes at 0°C, after which time urea (0.55 g, 0.009 mol) and cold water (50 ml) were added. Next, the reaction mixture was carefully added to a refluxing mixture of sulfuric acid (28ml) in water (115ml) and the reaction was stirred at reflux for a further 10 minutes before being allowed to cool to room temperature. After standing, an orange precipitate was observed which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder.

7-methoxy-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one : to 7-hydroxy-2-isopropyl-4-bromo-2H- K ₂ CO ₃ (0.59 g, 4.3 mmol) and methyl iodide (0.22 g, 1.55 mmol) and the mixture was heated to reflux for 24 hours. After this time, LC-MS showed complete consumption of starting material, and the reaction mixture was concentrated under vacuum. The residue was redissolved in EtOAc (50ml) and washed with water (2 x 30ml), the organic layer was dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.32g, 76% yield), which For orange powder.

Next, this material was used in the Buchwald reaction as described in Method A to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy -2H-2,3-phthalazin-1-one (Example G-1).

Using the experimental conditions reported above (Method G) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) G-1 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 12.07(1H,s), 9.27(1H,s), 8.56(1H,d), 7.85(1H,s), 7.63(1H,d), 6.52(1H,s), 5.46-5.39(1H,m), 4.10(3H,s), 2.86(3H,s), 1.50(6H,d) 314.32 G-2 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(pyridin-2-ylmethoxy)-2H-2,3-naphthyridine-1 -ketone (250MHz, D ₆ -DMSO) 9.12(1H,br s), 8.62-8.58(1H,m), 8.40(1H,d), 7.89-7.81(1H,m), 7.74(1H,d), 7.59- 7.52(2H, m), 7.40-7.33(1H, m), 6.32(1H, s), 5.38(2H, s), 5.29-5.13(1H, m), 2.23(3H, s), 1.31(6H, d) 391 G-3 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(pyridin-3-ylmethoxy)-2H-2,3-naphthyridine-1 -ketone (250MHz, D ₆ -DMSO) 9.13 (1H, br s), 8.73 (1H, d), 8.57 (1H, dd), 8.41 (1H, d), 7.96-7.89 (1H, m), 7.80 (1H, d), 7.55(1H,dd), 7.49-7.41(1H,m), 6.33(1H,s), 5.36(2H,s), 5.31-5.19(1H,m), 2.24(3H,s), 1.32 (6H, d) 391 G-4 2-isopropyl-4-(5-methyl (250MHz, D ₆ -DMSO) 9.13 (1H, 391.21

Base-1H-pyrazol-3-ylamino)-7-(pyridin-4-ylmethoxy)-2H-2,3-naphthyridine-1-one br s), 8.64-8.58 (2H, m), 8.42 (1H, d), 7.76 (1H, d), 7.58 (1H, dd), 7.52-7.46 (2H, m), 6.34 (1H, s), 5.41(2H, s), 5.32-5.18(1H, m), 2.24(3H, s), 1.32(6H, d) G-5 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholin-4-yl-ethoxy)-2H-2,3-diazepine Xinaphthin-1-one (250MHz, D ₆ -DMSO) 9.09(1H, br s), 8.38(1H, d), 7.69(1H, d), 7.46(1H, dd), 6.33(1H, s), 5.31-5.17(1H, m), 4.27(2H, t), 3.62-3.55(4H, m), 3.41(4H, opaque), 2.75(2H, t), 2.24(3H, s), 1.32(6H, d) 413.28 G-6 7-Hydroxy-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.84(1H,s), 10.59(1H,s), 8.99(1H,s), 8.27(1H,d), 7.58(1H,d), 7.25(1H,dd), 6.32(1H, s), 5.28-5.16(1H, m), 2.23(3H, s), 1.30(6H, d) 300.33 G-7 7-Difluoromethoxy-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, DMSO), 12.03(1H, br s), 9.31(1H, br s), 8.61(1H, d), 7.62-7.49(1H, m), 7.43(1H, s), 6.41(1H, s ), 5.37-5.22 (1H, m), 2.29 (3H, s), 1.40 (6H, d) 350.13 G-8 2-Benzyl-7-methoxy-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 9.46(1H, s), 8.35(1H, d), 7.84(1H, s), 7.55-7.38(5H, m), 6.24(1H, s), 5.35(2H, s), 4.08 (3H, s), 5.85 (3H, s) 362.30

G-9 2-isopropyl-6-methoxy-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, DMSO) 11.97(1H, br s), 9.16(1H, s), 8.24(1H, d), 7.96(1H, s), 7.42(1H, d), 6.39(1H, s), 5.34- 5.28(1H,m), 3.98(3H,s), 2.30(3H,s), 1.37(6H,d) 314.20

Method H:

Example H-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthio-2H-2,3-naphthyridine-1- ketone

7-Mercapto-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one : Concentrated sulfuric acid (5ml) was added dropwise to 7-amino-2-isopropyl-4 -Bromo-2H-2,3-phthalazin-1-one (1.5 g, 5.3 mmol) in a solution of HOAc (15 ml), and the solution was cooled to 0°C. A solution of _NaNO2 (0.5g, 7.4mmol) in water (2.5ml) was added dropwise and the reaction mixture was stirred at 0°C for 20 minutes, then urea (0.17g, 2.8mmol) was added in one portion. Then, the reaction mixture was added dropwise to an aqueous solution (7.5 ml) of potassium ethyl xanthate (6 g, 37.7 mmol), and the mixture was heated to 80° C. for 30 minutes. After this time, the reaction mixture was cooled to room temperature and DCM (100ml) was added. The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo.

The residue was taken up in THF (10ml), NaOH (4.95g, 0.12mmol) was added in one portion and the mixture was heated to reflux for 24 hours. Next, the mixture was cooled to room temperature, and the suspension was acidified to pH 2 with concentrated HCl. DCM (100ml) was added, the organic layer was separated and then washed with HCl (1M, 20ml) and water (20ml). The organic layer was extracted with NaOH (1M, 200ml), the aqueous layer was separated and acidified to pH 1 with concentrated HCl. The mixture was extracted with DCM (2 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.77g, 48% yield) as a light brown solid without It was directly used after further purification.

7-Methylthio-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one :

NaH ( 60%, 0.13 g, 3.1 mmol). After stirring for 5 minutes, methyl iodide (0.44 g, 3.1 mmol) was added dropwise and stirring was continued for 4 hours. The mixture was concentrated under vacuum and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 8.02(1H,d), 7.88(1H,d), 7.75(1H,d), 5.26-5.15(1H,m), 2.59(3H,s) , 1.35 (6H,d).

This material was then used in a Buchwald reaction as described in Method A to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthio -2H-2,3-phthalazin-1-one (Example H-1). ¹ H-NMR: (400MHz, D ₆ -DMSO), 11.92 (1H, s), 9.16 (1H, s), 8.36 (1H, d), 8.01 (1H, d), 7.75 (1H, d), 6.35 (1H, s), 5.29-5.19 (1H, m), 2.62 (3H, s), 2.25 (2H, s), 1.32 (6H, d) MS (ESI ⁺ ) = (M + H) ⁺ 330.26.

Example H-2: 2-isopropyl-7-methanesulfonyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1- ketone

2-isopropyl-7-methylsulfonyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one:

Potassium monopersulfate (0.88 g, 1.4 mmol) was added in one portion to 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthio-2H- 2,3-Naphthyridine-1-one (0.12 g, 0.36 mmol) was in a 4:1 mixture of dioxane/water (1.2 ml) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5ml) and the solution was extracted with EtOAc (3 x 75ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo to give a dark brown solid. Flash column chromatography (elution: 96% DCM, 4% MeOH) gave the title compound (0.032 g, 25% yield) as a pale yellow solid (Example H-2). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.99 (1H, br s), 9.44 (1H, s), 8.76-8.68 (2H, m), 8.39 (1H, d), 6.36 (1H, s) , 5.32-5.18 (1H, m), 3.36 (3H, s), 2.25 (3H, s), 1.34 (6H, d) MS (ESI ⁺ ) = (M + H) ⁺ 362.16.

Using the experimental conditions reported above (Method H, Example H-1 or H-2) and appropriate starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) H-3 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholin-4-yl-ethylthio)-2H-2,3-diazepine Xinaphthin-1-one (250MHz, D ₆ -DMSO) 9.15(1H, s), 8.35(1H, d), 8.08(1H, d), 7.79(1H, dd), 6.34(1H, s), 5.31-5.16(1H, m ), 3.61-3.54(4H, m), 3.33-3.24(2H, m), 2.62(2H, t), 2.48-2.40(4H, m), 2.24(3H, s), 1.32(6H, d) 429.16

Method I:

Example I-1: 2-isopropyl-7-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-(5-methyl-1H-pyrazole-3- Amino)-2H-2,3-naphthyridine-1-one

Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-tert-butyl carbamate:

7-Amino-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one (1.88 g, 6.7 mmol) was dissolved in dimethylformamide (DMF) (20 ml) . To this was added NaH (60%, 0.8 g, 20.1 mmol) as a suspension in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, then di-tert-butyl dicarbonate (Boc ₂ O) (4.36 g, 20.1 mmol) was added in one portion, and the reaction mixture was heated to 70° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was carefully added, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo.

The residue was dissolved in a 1:1 mixture of THF/EtOH (10 ml) and aqueous NaOH (50 wt % solution, 10 ml) was added in one portion and the reaction mixture was stirred vigorously for 30 min. After this time, the mixture was partitioned between water (20ml) and EtOAc (50ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to give the title compound (2.2 g, 88% yield) as a light brown solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 8.32(1H,d), 8.19(1H,s), 7.88(1H,d), 7.41(1H,s), 5.46-5.31(1H,m) , 1.52(9H, s), 1.41(6H, d) MS(ESI ⁺ )=(M+H) ^+382.22 .

4-Bromo-2-isopropyl-7-methylamino-2H-2,3-naphthyridine-1-one :

Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-carbamate tert-butyl ester (2.2 g, 5.7 mmol) was dissolved in in THF (10ml). To this was added NaH (60%, 0.34 g, 8.6 mmol) as a suspension in THF (5 ml). The mixture was stirred at room temperature for 30 minutes, then methyl iodide (1.4 ml, 23.0 mmol) was added in one portion as a solution in THF (5 ml), and the reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was added carefully, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo.

The residue was dissolved in 20% TFA/DCM solution (10 ml) and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was concentrated under vacuum to give a brown oil. Heptane (20ml) was added and the mixture concentrated in vacuo. Diethyl ether (10ml) was added to the residue and the resulting precipitate was filtered and dried under vacuum to give the title compound (1.14g, 68% yield) as a light brown solid. MS (ESI ⁺ ) = (M + H) ⁺ 296.16.

4-Bromo-2-isopropyl-7-[methyl-(2-morpholin-4-yl-ethyl)-amino]-2H-2,3-naphthyridine-1-one:

4-Bromo-2-isopropyl-7-methylamino-2H-2,3-naphthyridine-1-one (0.13 g, 0.44 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.053 g, 1.3 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 30 minutes, then 4-(2-chloro-ethyl)-morpholine (0.12 g, 0.66 mmol) was added in one portion as a solution in DMF (1 ml), and the reaction mixture was Heat to 70°C for 24 hours. After this time, the reaction mixture was cooled to room temperature and water (10ml) was added carefully, the mixture was extracted with EtOAc (3 x 10ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo. Flash column chromatography (elution: 95% EtOAc, 5% MeOH) gave the title compound (0.051 g, 30% yield) as a white solid. ¹ H-NMR: (400MHz, CDCl ₃ ), 7.72 (1H, d), 7.49 (1H, s), 7.16 (1H, d), 5.42-5.29 (1H, m), 3.73-3.67 (4H, m) , 3.66-3.59 (2H, t), 3.15 (3H, s), 2.61-2.54 (2H, m), 2.53-2.46 (4H, m), 1.41 (6H, d).

This material was then used in a Buchwald reaction as described in Method A to give the corresponding 2-isopropyl-7-[methyl-(2-morpholin-4-yl-ethyl)-amino ]-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (Example I-1).

Using the experimental conditions reported above (Method I) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) I-1 2-isopropyl-7-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-(5-methyl-1H-pyrazol-3-ylamino)-2H- 2,3-Naphthyridine-1-one (400MHz, D ₆ -DMSO), 11.81(1H, br s), 8.89(1H, br s), 8.19(1H, d), 7.33(1H, d), 7.23(1H, dd), 6.31(1H, s), 5.28-5.19(1H, m), 3.61(2H, t), 3.57-3.53(4H, m), 3.05(3H, s), 2.48-2.45(2H, m), 2.44-2.40(4H, m), 2.22(3H, s), 1.29(6H, d) 426.24 I-2 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(methyl-pyridin-4-ylmethyl-amino)-2H-2,3-diazepine Xinaphthin-1-one (250MHz, CD ₃ OD), 8.46(2H, d), 7.96(1H, d), 7.51(1H, d), 7.34-7.22(4H, m), 6.32(1H, s), 5.43-5.23(1H , m), 4.83(2H, s), 3.28(3H, s), 2.29(3H, s), 1.40(6H, d) 404.28 I-3 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(methyl-pyridin-3-ylmethyl-amino)-2H-2,3-diazepine Xinaphthin-1-one (400MHz, D ₆ -DMSO), 9.29(1H,br s), 8.73-8.67(2H,m), 8.18(1H,d), 8.10(1H,d), 7.78(1H,dd), 7.41-7.33 (2H,m), 6.36(1H,s), 5.27-5.16(1H,m), 4.95(2H,s), 3.24(3H,s), 2.26(3H,s), 1.30(6H,d) 404.33 I-4 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(methyl-pyridin-2-ylmethyl-amino)-2H-2,3-diazepine Xinaphthin-1-one (400MHz, D ₆ -DMSO), 9.24(1H, br s), 8.63(1H, d), 8.15(1H, d), 7.91(1H, t), 7.46-7.40(1H, m), 7.36(1H , d), 7.34-7.28 (2H, m), 6.35 (1H, s), 5.25-5.15 (1H, m), 4.92 (2H, s), 3.26 (3H, 404.32

s), 2.26(3H, s), 1.29(6H, d) I-5 N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 -yl]-N-methyl-acetamide (400MHz, D ₆ -DMSO), 11.92(1H,s), 9.23(1H,s), 8.48(1H,d), 8.13(1H,d), 7.87(1H,dd), 6.35(1H,s) , 5.31-5.16(1H, m), 3.28(3H, s), 2.24(3H, s), 1.94(3H, s), 1.32(6H, d) 355.33 I-6 3-isopropyl-1-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yl]-1-methyl-urea (400MHz, D ₆ -DMSO), 11.88(1H,br s), 9.15(1H,s), 8.36(1H,d), 8.03(1H,d), 7.78(1H,dd), 6.48(1H,d ), 6.34(1H, s), 5.32-5.18(1H, m), 3.91-3.76(1H, m), 3.28(3H, s), 2.24(3H, s), 1.32(6H, d), 1.10( 6H, d) 398.34 I-7 [3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl ]-methyl-urethane (400MHz, D ₆ -DMSO) 12.16-11.60 (1H, m), 9.23 (1H, s), 8.49 (1H, d), 8.23 (1H, s), 7.95 (1H, d), 6.43 (1H, s ), 5.48-5.13(1H, m), 4.21(2H, q), 3.42(3H, s), 2.31(3H, s), 1.39(6H, d), 1.27(3H, t) 385.13 I-8 N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 -yl]-acetamide (250MHz, D ₆ -DMSO) 10.50(1H,s), 9.11(1H,s), 8.51(1H,d), 8.37(1H,d), 8.06(1H,dd), 6.34(1H,s), 5.32-5.17(1H, m), 2.25(3H, s), 2.13(3H, s), 1.32(6H, d) 341.41 I-9 7-[(4-fluoro-benzyl)-methyl-amino]-2-isopropyl-4-(5-methyl-1H- (400MHz, D ₆ -DMSO) 8.99 (1H, s), 8.18 (1H, d), 7.35 (1H, d), 7.28 (1H, dd), 7.26-7.20 (2 421.40

Pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one H, m), 7.19-7.11 (2H, m), 6.32 (1H, s), 5.28-5.16 (1H, m), 4.76 (2H, s), 3.18 (3H, s), 2.23 (3H, s) , 1.29 (6H, d) I-10 N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 -yl]-N-methyl-methanesulfonamide (400MHz, DMSO) 11.94 (1H, br.s.), 9.23 (1H, br.s.), 8.48 (1H, d), 8.23 (1H, d), 7.91 (1H, dd), 6.36 (1H, s), 5.30-5.21(1H, m), 3.38(3H, s), 3.03(3H, s), 2.25(3H, s), 1.32(6H, d) 391.35 I-11 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholin-4-yl-ethylamino)-2H-2,3-diazepine Xinaphthin-1-one (250MHz, D ₆ -DMSO), 9.64(1H,br s), 8.91(1H,s), 8.09(1H,d), 7.27(1H,d), 7.07(1H,d), 6.71(1H,br s), 6.25(1H, s), 5.20-5.13(1H, m), 3.95-3.92(2H, m), 3.29-3.27(4H, m), 3.11-3.08(2H, m), 2.17(3H, s), 1.23 (6H, d) 412.37 I-12 2-isopropyl-7-methylamino-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 9.04(1H, br s), 8.08(1H, d), 7.19(1H, d), 7.06(1H, dd), 6.33(1H, d), 5.29-5.19(1H , m), 2.80(3H, s), 2.26(3H, s), 1.30(6H, d) 313.18 I-13 1-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 -yl]-3-methyl-urea (400MHz, D ₆ -DMSO), 8.98(1H, s), 8.91(1H, s), 8.06(1H, s), 8.03(1H, s), 7.71(1H, d), 6.12(1H, s) , 6.05(1H,s), 5.05-4.97(1H,m), 2.45(3H,s), 2.03(3H,s), 1.10(6H,d) I-14 [3-isopropyl-1-(5-methyl (250MHz, DMSO), 9.31 (1H, br 413.18

Base-2H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl]-methyl-carbamic acid tert-butyl ester s), 8.37(1H,d), 8.15(1H,d), 7.87(1H,dd), 6.36(1H,s), 5.31-5.15(1H,m), 3.32(3H,s), 2.26(3H ,s), 1.44(9H,s), 1.32(6H,d)

According to Method J, Example I-13 was synthesized as in Example J-1.

Method J:

Example J-1: 1-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yl]-3-methyl-urea

1-(1-Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-3-methyl-urea :

7-Amino-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one (0.5 g, 1.77 mmol) was dissolved in THF (5 ml). To this was added NaH (60%, 0.14 g, 3.54 mmol) as a suspension in THF (2 ml), and the reaction mixture was stirred for 5 minutes. After this time, methyl isocyanate (0.2 g, 3.55 mmol) was added in one portion and the reaction mixture was stirred at room temperature for a further 48 hours. After this time, the reaction mixture was partitioned between EtOAc (50ml) and water (50ml), the organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.47g, 78% yield), which It is a light brown solid.

This material was then used in the Buchwald reaction, as described in Method A, to give the corresponding 1-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino) -4-Oxo-3,4-dihydro-2,3-phthalazin-6-yl]-3-methyl-urea (Example J-1).

Using the experimental conditions reported above (Method J) and suitable starting materials, the following derivatives were prepared:

Example number system naming ¹ H-NMR MS (ESI+, M+H) J-1 1-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 - (400MHz, D ₆ -DMSO), 8.98(1H,s), 8.91(1H,s), 8.04(1H,d), 7.70(1H,dd), 6.12(1H,s), 6.04(1H,s) , 5.05-4.97 (1H,

]-3-methyl-urea m), 2.47(3H, d), 2.03(3H, s), 1.09(6H, d) J-2 N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6 -yl]-methanesulfonamide (400MHz, D ₆ -DMSO), 10.49(1H, br s), 9.34(1H, s), 8.43(1H, d), 8.11(1H, s), 6.36(1H, s), 5.32-5.19(1H , m), 3.15(3H, s), 2.25(3H, s), 1.33(6H, d) 377.24

Method K:

Example K-1: 2-isopropyl-7-methoxymethyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine- 1-keto

1,4-Dioxo-1,2,3,4-tetrahydro-2,3-naphthyridine-6-carboxylic acid : At room temperature, hydrazine hydrate (26 g, 0.52 mol) was A stirred mixture of 1,2,4-benzenetricarboxylic anhydride (100 g, 0.52 mol) in HOAc (1.0 L) was added. The mixture was heated to 120 °C for 2 hours, then allowed to cool to room temperature. The solid was filtered, washed with water (250ml) and dried in a vacuum oven at 50°C for 20 hours to give the title compound (91g, 85% yield).

Bromo-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid: 1,4-dioxo-1,2,3,4-tetrahydro-2 , 3-Naphthalene-6-carboxylic acid (91.0 g, 0.44 mol) was suspended in DCE (1.0 L), phosphorus pentabromide (761.0 g, 1.77 mol) was added in three portions and the reaction was heated to Reflux for 24 hours. The reaction was cooled to room temperature and poured onto ice (2.50 kg), the resulting precipitate was filtered and washed with water to give the crude product (130 g).

The crude material was suspended in HOAc (1.60 L) and heated to 125 °C for 2 hours. The reaction was cooled to room temperature and poured onto ice (1.5 kg) and the resulting precipitate was filtered. The solid was washed with water and dried to give the title compound (85 g, 73% yield) as a yellow solid. MS (ESI ⁺ ) = (M + H) ⁺ 310 & 312

Bromo-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid ethyl ester : Add concentrated sulfuric acid (40ml) to 1-bromo-4-oxo-3 , a stirred solution of 4-dihydro-2,3-naphthyridine-6-carboxylic acid (85 g, 0.32 mol) in EtOH (500 ml), and the mixture was heated to reflux for 48 hours. After this time, the reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was partitioned between EtOAc (1 L) and saturated NaHCO ₃ (500 ml), the organic layer was separated and washed with water (500 ml), then dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound (30 g , 31% yield) as a white solid. MS(ESI ⁺ )＝(M+H) ⁺ 297 & 299

Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid ethyl ester : Bromo-4-oxo-3,4- Ethyl dihydro-2,3-naphthyridine-6-carboxylate (6 g, 0.02 mol) was dissolved in DMF (60 ml). To this was added NaH (60%, 0.97 g, 0.024 mol) as a DMF suspension (5 ml). The mixture was stirred at room temperature for 30 minutes, then 2-bromo-propanol (3.7 g, 0.03 mol) was added in one portion as a solution in DMF (5 ml). The reaction mixture was stirred for 48 hours, after which time LC-MS showed complete consumption of starting material. DMF was removed under vacuum and the resulting residue was partitioned between DCM (100ml) and water (100ml), the organic layer was dried ( _MgSO4 ), filtered and concentrated under vacuum. The resulting yellow oil was recrystallized from MeOH to give the title compound (2.3 g, 34% yield) as a white solid. MS (ESI ⁺ ) = (M + H) ⁺ 339 & 341

4-Bromo-7-hydroxymethyl-2-isopropyl-2H-2,3-naphthyridine-1-one : Bromo-3-isopropyl-4-oxo-3,4 - Ethyl dihydro-2,3-naphthyridine-6-carboxylate (2.3 g, 6.8 mmol) was suspended in THF (50 ml) and cooled to 0°C. To the suspension was added _LiBH4 (5.1 ml of a 2M solution in THF, 10.2 mmol) dropwise, and the suspension was allowed to warm to room temperature and stirred for 24 hours. After this time, LC-MS showed 50% of starting material remained. To this was added _LiBH4 (1.7 ml of a 2M solution in THF, 3.4 mmol), and the reaction mixture was stirred for a further 3 hours. The reaction was cooled to 0°C, saturated _NH4Cl (40ml) was added and the reaction mixture was then partitioned between water (50ml) and DCM (150ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting residue was then purified by flash column chromatography (elution: 50% toluene, 30% EtOAc, 20% DCM) to give the title compound (0.9 g, 43% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 8.28(1H, s), 7.96(1H, d), 7.88(1H, d), 5.64(1H, t), 5.31-5.18(1H, m) , 4.78 (2H, d), 1.35 (6H, d); MS (ESI ⁺ ) = (M + H) ⁺ 297 & 299

4-bromo-2-isopropyl-7-methoxymethyl-2H-2,3-naphthyridine-1-one : 4-bromo-7-hydroxymethyl-2-isopropyl Ethyl-2H-2,3-phthalazin-1-one (0.11 g, 0.37 mmol) was dissolved in THF (2 ml). To this was added NaH (60%, 0.019 g, 0.44 mmol) as a THF suspension (2 ml). To this was added methyl iodide (0.063 g, 0.48 mmol) and the reaction mixture was stirred for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.08 g, 69% yield) as a white solid.

This material was then used in the Buchwald reaction, as described in Method A, to give the corresponding 2-isopropyl-7-methoxymethyl-4-(5-methyl-1H-pyrazole- 3-ylamino)-2H-2,3-naphthyridine-1-one (Example K-1).

Using the experimental conditions reported above (Method K) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) K-1 2-Isopropyl-7-methoxymethyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, DMSO), 11.88(1H, br s), 9.18(1H, br s), 8.42(1H, d), 8.23(1H, br s), 7.80(1H, d), 6.35(1H, s) , 5.30-5.20(1H, m), 4.62(2H, s), 2.24(3H, s), 1.32(6H, d) 328.31 K-2 Isopropyl-6-methoxy-methyl-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one 376.30 K-3 2-Benzyl-7-methoxy-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, DMSO), 11.93(1H,s), 9.19(1H,s), 8.43(1H,s), 8.27(1H,d), 7.79(1H,d), 6.37(1H,s), 5.30- 5.20(1H,m), 4.61(2H,s), 3.37(3H,s), 2.25(3H,s), 1.33(6H,d) 328.31

Method L:

Example L-1: 2-isopropyl-7-(4-methyl-piperazin-1-ylmethyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H -2,3-naphthyridine-1-one

4-bromo-7-bromomethyl-2-isopropyl-2H-2,3-naphthyridine-1-one : 4-bromo-7-hydroxymethyl-2-isopropyl - A solution of 2H-2,3-phthalazin-1-one (0.74 g, 2.5 mmol) in MeCN (5 ml) was added dropwise to trimethylsilyl bromide (TMSBr) (0.9 g, 6.3 mmol) and a stirred suspension of LiBr (0.41 g, 5 mmol) in MeCN (15 ml). The reaction mixture was heated to 80 °C for 24 hours, then the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The resulting residue was purified by flash column chromatography (elution: 85% heptane, 15% EtOAc) to give the title compound (0.4 g, 44% yield) as a white solid. ¹ H-NMR: (250MHz, D ₆ -DMSO), 8.37 (1H, s), 8.03 (1H, d), 7.94 (1H, d), 5.26-5.09 (1H, m), 4.93 (2H, s) , 1.35 (6H,d).

4-bromo-2-isopropyl-7-(4-methyl-piperazin-1-ylmethyl)-2H-2,3-phthalazin-1-one : 4-bromo- 7-Bromomethyl-2-isopropyl-2H-2,3-phthalazin-1-one (0.2g, 0.56mmol) was dissolved in THF (1ml) and added as N-methylpiperazine (0.14 g, 1.4 mmol) was dissolved in N-methylpiperazine and the reaction mixture was stirred for 1 hour. Subsequent LC-MS showed complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 90% EtOAC, 10% MeOH) to give the title compound (0.17 g, 84% yield ), which is a pale yellow solid.

This material was then used in the Buchwald reaction, as described in Method A, to give the corresponding 2-isopropyl-7-(4-methyl-piperazin-1-ylmethyl)-4-( 5-Methyl-1H-pyrazol-3-ylamino)-2H-2,3-phthalazin-1-one (Example L-1).

Using the experimental conditions reported above (Method L) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) L-1 2-isopropyl-7-(4-methyl-piperazin-1-ylmethyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-di Aziridine-1-one (250MHz, D ₆ -DMSO), 9.16(1H, br s), 8.40(1H, d), 8.20(1H, d), 7.80(1H, d), 6.36(1H, s), 5.32-5.21(1H , m), 3.65(2H, s), 2.45-2.28(8H, m), 2.25(3H, s), 2.16(3H, s), 1.32(6H, d) 396.33

L-2 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-morpholin-4-ylmethyl-2H-2,3-naphthyridine-1-one (250MHz, D ₆ -DMSO), 9.20(1H,br s), 8.41(1H,d), 8.23-8.19(1H,m), 7.81(1H,dd), 6.34(1H,s), 5.33-5.17 (1H, m), 3.66 (2H, s), 3.62-3.54 (4H, m), 2.43-2.34 (4H, m), 2.24 (3H, s), 1.32 (6H, d) 383.31

Method M:

Example M-1: 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-diazepine Naphthalene-6-carboxylic acid

3-{tert-butoxycarbonyl-[6-(tert-butyl-dimethyl-silyloxymethyl)-3-isopropyl-4-oxo-3,4- dihydro-2,3- Naphthalene-1-yl]-amino}-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester :

7-(tert-butyl-dimethyl-silyloxymethyl)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3 - Naphthalene-1-one (0.68g, 1.59mmol) was dissolved in DMF (20ml). To this was added NaH (60%, 0.22 g, 5.56 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 15 minutes, then di-tert-butyl dicarbonate (Boc20) (1.05 g, 5.56 mmol) in DMF ( ₂ ml) was added in one portion and the reaction mixture was stirred at room temperature for 3 hours . After this time, the reaction mixture was concentrated under vacuum and the resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% EtOAc) to give the title compound (0.78 g, 78% yield) as a brown Oil. MS (ESI ⁺ ) = (M + H) ⁺ 628.51.

3-[tert-butoxycarbonyl-(6-hydroxymethyl-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthyridine- 1-yl)-amino]- 5-Methyl-pyrazole-1-carboxylic acid tert-butyl ester : 3-{tert-butoxycarbonyl-[6-(tert-butyl-dimethyl-silyloxymethyl)-3-isopropyl -4-oxo-3,4-dihydro-2,3-naphthalene-1-yl]-amino}-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.78, 1.25mmol ) was dissolved in THF (3ml), to which was added a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (1.87ml, 1.87mmol) and the mixture was stirred at room temperature for 24 hours. After this time, the reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 50% heptane, 50% EtOAc) to give the title compound (0.39 g, 45% yield) as a brown solid . MS (ESI ⁺ ) = (M + H) ⁺ 514.43.

1-[tert-butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo- 3,4-di Hydrogen-2,3-naphthyridine-6-carboxylic acid : 3-[tert-butoxycarbonyl-(6-hydroxymethyl-3-isopropyl-4-oxo-3,4-dihydro- 2,3-Pyrazole-1-yl)-amino]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.2 g, 0.39 mmol) was dissolved in DMSO (3 ml). To this was added 2-iodobenzoic acid (IBX) (0.22 g, 0.78 mmol) in one portion and the reaction mixture was stirred at room temperature for 24 hours. After this time the reaction mixture was partitioned between EtOAc (20ml) and water (20ml), the organic layer was separated, washed with water (3 x 20ml) then dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting orange oil (0.197g, 0.38mmol) was dissolved in DCM (3ml) and water (3ml). To this was added sulfamic acid (0.037 g, 0.38 mmol) and the reaction mixture was vigorously stirred at 0°C. After 5 minutes, sodium chlorite (0.034 g, 0.38 mmol) was added in one portion and the mixture was stirred for a further 1 hour. After this time, the reaction mixture was diluted with DCM (20ml) and washed with water (10ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% EtOAc-100% EtOAc) to afford the title compound (0.088 g, 44% yield) as a white solid. MS (ESI ⁺ ) = (M + H) ⁺ 528.41.

Isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine- 6-carboxylic acid : the 1-[tert-butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-di Hydrogen-2,3-naphthyridine-6-carboxylic acid (13.0 mg, 0.02 mmol) was dissolved in 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to afford the title compound (Example M-1 ) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 9.34 (1H, s), 8.73 (1H, s), 8.47 (1H, d), 8.26 (1H, d), 6.28 (1H, s), 5.20 -5.17 (1H, m), 2.19 (3H, s), 1.26 (6H, d) MS (ESI ⁺ ) = (M + H) ⁺ 328.31.

Example M-2: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(morpholine-4-carbonyl)-2H-2,3-diazepine Xinaphthin-1-one

Isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(morpholine-4-carbonyl)-2H-2,3-naphthyridine- 1-one : the 1-[tert-butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-di Hydrogen-2,3-naphthyridine-6-carboxylic acid (13 mg, 0.025 mmol) was dissolved in DMF (2 ml). Morpholine (6.4 mg, 0.075 mmol) was added thereto and the reaction mixture was cooled to 0° C., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylium tetra Fluoborate (TBTU) (15 mg, 0.03 mmol) and TEA (0.014 ml, 0.1 mmol) were added continuously and the reaction mixture was stirred at room temperature for 24 hours. After this time, the reaction mixture was partitioned between EtOAc (10ml) and water (10ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting residue (13.0 mg, 0.02 mmol) was dissolved in 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(morpholine -4-Carbonyl)-2H-2,3-naphthyridine-1-one (Example M-2). ^.1 H-NMR: (400MHz, D ₆ -DMSO) 9.40(1H,s), 8.50(1H,d), 8.23(1H,s), 7.91(1H,d), 6.36(1H,s), 5.28 -5.21 (1H, m), 4.12-3.30 (8H, opaque) 2.26 (3H, s), 1.33 (6H, d) MS (ESI ⁺ ) = (M + H) ⁺ 397.21.

Using the experimental conditions reported above (Method M, Example M-2) and suitable starting materials, the following derivatives were prepared:

Example number system naming ¹ H-NMR MS (ESI+, M+H) M-3 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid diethylamide (400MHz, D ₆ -DMSO), 9.46(1H, s), 8.46(1H, d), 8.17(1H, s), 7.88(1H, d), 6.37(1H, s), 5.26-5.23(1H, m), 3.48-3.47 (2H, m), 3.18-3.16 (2H, m), 2.27 (3H, s), 1.34 (6H, d), 1.18-1.15 (3H, m), 1.08-1.01 (3H, m) 383.16 M-4 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-di (400MHz, D ₆ -DMSO), 12.16(1H, br s), 9.39(1H, s), 8.66(1H, s), 8.51(1H, d), 8.21(1H, 357.12

Hydrogen-2,3-naphthyridine-6-carboxylic acid methoxy-amide d), 6.36(1H, s), 5.28-5.22(1H, m), 3.75(3H, s), 2.26(3H, s), 1.33(6H, d) M-5 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid Isopropylamide (400MHz, D ₆ -DMSO)9.43(1H,br.s.), 8.76(1H,d), 8.70(1H,d), 8.49(1H,d), 8.31(1H,dd), 6.38(1H, s), 5.31-5.22(1H, m), 4.21-4.09(1H, m), 2.27(3H, s), 1.34(6H, d), 1.20(6H, d) 369.37 M-6 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid Cyclopropyl methyl ester (400MHz, D ₆ -DMSO)9.36(1H,s), 8.83(1H,d), 8.60(1H,d), 8.36(1H,dd), 6.35(1H,s), 5.33-5.16(1H,m ), 4.21(2H, d), 2.25(3H, s), 1.33(6H, d), 1.25-1.21(1H, m), 0.65-0.56(2H, m), 0.45-0.34(2H, m) 382.36 M-7 7-(4-Acetyl-piperazine-1-carbonyl)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diaze Xinaphthin-1-one (400MHz, D ₆ -DMSO) 9.30(1H, s), 8.51(1H, d), 8.25(1H, d), 7.90(1H, dd), 6.34(1H, s), 5.32-5.16(1H, m ), 2.24(3H, s), 2.01(3H, d), 1.32(6H, d) 438.40

Example M-8: 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-diazepine Methyl naphthalene-6-carboxylate

1-[tert-butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4- Dihydro-2,3-naphthyridine-6-carboxylic acid (10 mg, 0.019 mmol) (intermediate of Example M-1) was dissolved in DCM (1 ml). To this was added _K2CO3 (3.1 mg, 0.028 _mmol ) followed by methyl iodide (3.3 mg, 0.028 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was partitioned between EtOAc (10ml) and water (10ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo.

The resulting residue was dissolved in 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to afford the title compound as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO), 12.16 (1H, br s), 9.39 (1H, s), 8.66 (1H, s), 8.51 (1H, d), 8.21 (1H, d), 6.36(1H, s), 5.28-5.22(1H, m), 3.75(3H, s), 2.26(3H, s), 1.33(6H, d) MS(ESI ⁺ ) = (M+H) ⁺ 357.12.

Example M-9: 7-Hydroxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1- ketone

Bromo-7-hydroxymethyl-2-isopropyl-2H-2,3-phthalazin-1-one (2.0 g, 6.73 mmol) was dissolved in DCM (15 ml). To this was added TEA (1.4ml, 10.09mmol) and DMAP (5mg). The mixture was stirred at room temperature for 5 minutes, then a solution of tert-butyldimethylsilyl chloride (TBSCl) (1.22 g, 8.07 mmol) in DCM (5 ml) was added dropwise and the reaction mixture was stirred at room temperature 24 hours. The reaction mixture was partitioned between DCM (100ml) and water (50ml), the organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give 4-bromo-7-(tert-butyl-dimethyl-silyloxymethyl)-2-isopropyl-2H-2,3-di Aziridine-1-one (2.54 g, 92% yield) as a white solid. MS (ESI ⁺ ) = (M + H) ⁺ 412 & 414

Next, this material was used in the Buchwald reaction as described in method A, and the residue was dissolved in a 1:1 THF/DCM solution (6 ml). TBAF on silica (0.35 g, 0.35 mmol) was added and the mixture was stirred at room temperature for 24 hours. After this time, the reaction mixture was filtered and the silica was washed with DCM (20ml). The solvent was removed under vacuum to give the corresponding 7-hydroxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine Naphthalen-1-one (Example M-9). ¹ H-NMR: (400MHz, D ₆ -DMSO), 9.12(1H,s), 8.40(1H,d), 8.26(1H,s), 7.79(1H,d), 6.37(1H,s), 5.51 (1H, t), 5.30-5.21 (1H, m), 4.69 (2H, d), 2.24 (3H, s), 1.32 (6H, d) MS (ESI ⁺ ) = (M + H) ⁺ 314.16.

Using the experimental conditions reported above (Method M, Example M-9) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (ESI+, M+H) M-10 6-Hydroxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 9.44(1H, br s), 8.32(1H, s), 8.26(1H, d), 7.82(1H, d), 6.38(1H, s), 5.29-5.19(1H , m), 4.71 (2H, s), 2.28 (3H, s), 1.33 (6H, d) 314.24

Method N:

Example N-1: 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-diazepine Naphthalene-6-carboxylic acid amide

Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carbonitrile: Slowly add concentrated hydrochloric acid (0.82ml) to 7-amino-2-iso Propyl-4-bromo-2H-2,3-naphthyridine-1-one (1.0 g, 3.55 mmol) suspension in water (4 ml). The reaction mixture was cooled to 0 °C and a solution of _NaNO2 (0.3 g, 4.30 mmol) in water (1 ml) was added dropwise. The mixture was cooled to -20°C, toluene (4ml) was added and the mixture was neutralized with saturated _NaHCO3 (5ml).

Simultaneously, a solution of KCN (1.5 g, 23.4 mmol) in water (3 ml) was added dropwise to a suspension of Cu(I)Cl in water (4 ml), the mixture was cooled to 0° C. and stirred for 1 h . After this time, EtOAc (8ml) was added followed by the diazo species prepared above in portions and the mixture was stirred for a further 1 hour before being cooled and filtered through celite. The filtrate was washed with water (5ml), saturated _NaHCO3 (5ml) and brine (5ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to afford the title compound (0.077 g, 8% yield) as an orange solid. MS(ESI ⁺ )＝(M+H) ⁺ 292 & 294.

This material was then used in the Buchwald reaction, as described in Method A, to give the corresponding 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4- Oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid amide (Example N-1).

Example N-1: 3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3-diazepine Naphthalene-6-carboxylic acid amide

¹ H-NMR: (400MHz, D ₆ -DMSO), 11.79 (1H, s), 9.12 (1H, s), 8.63 (1H, s), 8.37 (1H, d), 8.22 (1H, s), 8.16 (1H, d), 7.52(1H, s), 6.20(1H, s), 5.21-4.95(1H, m), 2.10(3H, s), 1.18(6H, d); MS(ESI ⁺ )=( M+H) ⁺ 327.30.

Method O

Example O-1: 2-(2-Methoxyethyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1- ketone

4-bromo-2-(2-methoxyethyl)-4-bromo-2H-2,3-naphthyridine-1-one : 4-bromo-2H-2,3-di Aziridine-1-one (see Method E, 2.25 g, 10 mmol) was dissolved in DMF (30 ml). To this was added NaH (60%, 0.27 g, 11 mmol) as a DMF suspension (10 ml). The mixture was stirred at 5°C for 30 minutes, then 1-bromo-2methoxyethane (1.67g, 12mmol) was added in one portion as a solution in DMF (10ml). The reaction mixture was stirred at room temperature for 24 hours after which it was poured into water (200ml). Extraction with EtOAc followed by drying the combined organic phases over _Na2SO4 , filtering the solids and stirring the collected precipitates in diethyl ether:heptane (1:1) gave the title compound (2.4 _g , 85% yield) , which is a white solid.

¹ H-NMR: (400MHz, D ₆ -DMSO) 8.30 (1H, d), 8.03-8.30 (1H, m), 7.94-7.99 (2H, m), 4.30 (2H, t), 3.71 (2H, t ), 3.25(3H, s).

4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(2-methoxy-ethyl)-2H-2,3- naphthyridine-1 - Ketone (typical method for Buchwald reaction): 4-bromo-2-(2-methoxyethyl)-4-bromo-2H-2,3-naphthyridine-1-one (0.57 g, 2.0mmol), 1-(tert-butyl)-3-methyl-1H-pyrazol-5-ylamine (0.46g, 3.0mmol), Cs ₂ CO ₃ (0.98mg, 3.0mmol), tri( Dibenzylideneacetone)-dipalladium(0) (0.092g, 0.1mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.17mg, 0.3mmol) were dissolved in In degassed dioxane (10ml). The reaction mixture was heated to 130° C. with stirring for 8 hours, then cooled to room temperature. Water (100ml) was added and the precipitated solid was filtered, washed with EtOAc and _H2O . The crude product was purified by silica gel (EtOAc:heptane 0%-60% EtOAc) to afford the title compound (0.46 g, 65% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.22-8.31 (3H, m), 7.95 (1H, t), 7.86 (1H, t), 5.91 (1H, s), 4.05 (1H, t), 3.55 (1H, t), 3.17 (3H, s), 2.14 (3H, s), 1.54 (9H, s); MS (ESI ⁺ ) = 356.3 (M+H) ⁺ .

2-(2-methoxyethyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (for tertiary Typical method for deprotection of butyl-protected pyrazoles): 4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(2-methoxy-ethyl yl)-2H-2,3-naphthyridine-1-one (0.36 g, 1.0 mmol) was dissolved in formic acid (20 ml) and heated at reflux for 4 hours. After evaporation of formic acid, the obtained crude product was dissolved in _H2O and DCM. Addition of NaHCO ₃ resulted in the precipitation of a solid which was collected by filtration. Subsequent washing with _H2O , DCM and diethyl ether and drying in vacuo at 40 °C yielded the desired 2-(2-methoxyethyl)-4-(5-methyl-2H-pyrazol-3-yl Amino)-2H-2,3-phthalazin-1-one product (Example O-1) (0.28 g, 94%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.21 (1H, s), 8.43 (1H, d), 8.29 (1H, d), 8.14 (1H, s), 7.84-7.94 (2H, m), 6.28(1H,s), 4.23(2H,t), 3.74(2H,t), 3.33(3H,s), 2.23(3H,s); MS(ESI ⁺ )=300.3(M+H) ⁺ .

Using the experimental conditions reported above (Method O) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) O-2 2-(2-methoxy-1-methyl-ethyl)-4-(5-methyl-2H-pyrazol-3-yl-amino)-2H-2,3-naphthyridine-1 -ketone (400MHz, D ₆ -DMSO) 11.96(1H,s), 9.18(1H,s), 8.43(1H,d), 8.29(1H,d), 7.83-7.91(2H,m), 6.27(1H,s ), 5.35(1H, m), 3.76(1H, t), 3.48(1H, m), 3.23(3H, s), 2.25(3H, s), 1.26(3H, d) 314.1

Example O-3: cis-2-(4-tert-butyl-cyclohexyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-diazepine Naphthalene-1-one

Cis-4-bromo-2-(4-tert-butyl-cyclohexyl)-2H-2,3-naphthyridine-1-one : 450mg 4-bromo-2H-2,3-di Aziridine-1-one (see method E), 469 mg trans-4-tert-butylcyclohexanol and 787 mg triphenylphosphine were dissolved in 50 ml toluene. At 5°C, 1.306 g of diethyl azodicarboxylate were added dropwise within 30 minutes. Stirring was continued at room temperature for 24 hours. 50 ml of water and 50 ml of EtOAc were added, the organic phase was separated and washed with water and sodium chloride solution. After drying and evaporation, the residue was chromatographed on silica eluting with a gradient of heptane to heptane/EtOAc 1:1. Yield 435 mg of the title product.

The 4-bromo-2,3-naphthyridine obtained above was coupled with 1-(tert-butyl)-3-methyl-1H-pyrazol-5-ylamine and then passed through as O-1 The formic acid treatment is deprotected to give cis-2-(4-tert-butyl-cyclohexyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one (Example O-3). MS (ESI, M-H) 378.2.

Method P

Example P-1: 2-(4-isopropyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1 -ketone

4-Hydroxy-2-(4-isopropylphenyl)-2H-2,3-naphthyridine-1-one : At RT, 4-isopropylphenylhydrazine hydrochloride (2.77 g, 14.6 mmol) was added in one portion to a stirred mixture of phthalic anhydride (2.0 g, 13 mmol) in HOAc (25 ml). The reaction mixture was heated to 125 °C for 2 hours, then allowed to cool to room temperature. The resulting suspension was poured into _H2O (100ml), _NaHCO3 solution (1M) was added and the resulting solid was removed by filtration. The mother liquor was acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo to give the title compound (1.62 g, 45% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.80 (1H, s), 8.30 (1H, d), 7.92-8.01 (3H, m), 7.92 (2H, d), 7.35 (2H, d), 2.96 (1H, m), 1.25 (6H, d); MS (ESI ⁺ ) = 345.12 (M + H) ⁺ .

4-Bromo-2-(4-isopropylphenyl)-2H-2,3-phthalazin-1-one : 4-hydroxy-2-(4-isopropylphenyl)-2H -2,3-naphthyridine-1-one (0.10g, 0.36mmol), phosphorus oxybromide (0.41g, 1.4mmol) and 2,6-di-tert-butyl-4-methylphenol (0.02 g, 0.09 mmol) was stirred at 150°C for 30 minutes. After cooling to room temperature _H2O (100ml) was added. Extraction with DCM, drying of the combined organic phases over _Na2SO4 and evaporation of the solvent yielded the desired compound (0.05 g, 41% ₎ which was used without further purification.

Next, this material was used in a Buchwald reaction with 1-(tert-butyl)-3-methyl-1H-pyrazol-5-ylamine, followed by acid-catalyzed deprotection of the tert-butyl group, as described in Methods O, to obtain the corresponding 2-(4-isopropyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-diazepine Naphthalen-1-one (Example P-1).

2-(4-isopropyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one : yield ( 0.004g, 21%); ¹ H-NMR: (400MHz, CDCl ₃ /MeOD), 8.50(1H,d), 8.22(1H,d), 7.97(1H,t), 7.91(1H,t), 7.63 (2H,d), 7.38(2H,d), 6.25(1H,s), 3.01(1H,m), 2.26(3H,s), 1.28(6H,d).

Using the experimental conditions reported above (Method P) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) P-2 2-(4-sec-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO)9.29(1H,s), 8.50(1H,d), 8.36(1H,d), 7.89-7.98(2H,m), 7.64(2H,d), 7.32(2H,d ), 6.22(1H, s), 2.67(1H, m), 2.19(3H, s), 1.62(2H, m), 1.24(3H, d), 0.84(3H, t) 374.13

Method Q - Suzuki coupling with 2-(iodophenyl)-2,3-naphthyridine

Example Q-1: 2-biphenyl-4-yl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one

4-Hydroxy-2-(4-iodophenyl)-2H-2,3-naphthyridine-1-one : 4-iodophenylhydrazine (8.97 g, 36.4 mmol) in one portion at room temperature To a stirred mixture of phthalic anhydride (5.0 g, 33 mmol) in HOAc (40 ml) was added. The reaction mixture was heated to 125°C for 2 hours, then allowed to cool to room temperature. The suspension was poured into _H2O (100ml) and the resulting solid was removed by filtration. The mother liquor was acidified with concentrated HCl. The resulting solid was collected by filtration and dried in vacuo to give the title compound (1.0 g, 8% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.91 (1H, br.s), 8.30 (1H, d), 7.91-8.03 (3H, m), 7.83 (2H, d), 7.51 (2H, d ); MS (ESI ⁺ ) = 365.0 (M + H) ⁺ .

2-biphenyl-4-yl-4-hydroxy-2H-2,3-phthalazin (phtalazin)-1-one : 4-hydroxy-2-(4-iodophenyl)-2H-2 , 3-naphthyridine-1-one (0.1 g, 0.3 mmol), phenylboronic acid (0.04 g, 3 mmol), palladium black (0.02 g, 0.2 mmol) and KF (0.1 g, 18 mmol) were dissolved in MeOH ( 2 ml) and heated at reflux for 7 hours. The supernatant palladium was removed by filtration, extracted with water and the precipitated solid was then filtered to give the desired title compound (0.07 g, 78% yield) as a white solid. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.88 (1H, s), 8.33 (1H, d), 7.89-8.03 (3H, m), 7.78-7.86 (6H, m), 7.50 (2H, t ), 7.39(1H, t),; MS(ESI ⁺ )=315.3(M+H) ⁺ .

Next, this material was brominated with neat phosphorus oxybromide, as described in Method R, and subsequently used in the Buchwald reaction, as described in Method A, to give the corresponding 2-biphenyl-4- yl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (Example Q-1).

2-biphenyl-4-yl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one : Yield (0.03g, 29%); ¹ H-NMR: (400MHz, D ₆ -DMSO), 9.36 (1H, s), 8.58 (1H, d), 8.45 (1H, d), 7.95 (3H, m), 7.87-7.92 ( 6H, m), 7.56(2H, t), 7.46(1H, t), 6.35(1H, s), 2.26(3H, s); MS(ESI ⁺ )=394.6(M+H) ⁺ .

Example Q-2: 2-(2'-methyl-biphenyl-4-yl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-di Aziridine-1-one

4-(1-tert-butyl-5-methyl-1H-pyrazol-3-ylamino)-2-(2'-methyl-biphenyl-4-yl)-2H-2,3-di Aziridine-1-one :

4-Bromo-2-(2'-methyl-biphenyl-4-yl)-2H-2,3-naphthyridine-1-one (from suitable (prepared from starting material) was coupled with 1-tert-butyl-5-methyl-1H-pyrazol-3-ylamine in a Buchwald reaction as described in Method O to afford the title compound (0.049 g, 31% yield ). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.44 (1H, s), 8.40 (1H, d), 8.33 (1H, d), 8.05 (1H, t), 7.97 (1H, t), 7.62 ( 2H, d), 7.40 (2H, d), 7.30 (2H, d), 7.24 (2H, d), 6.00 (1H, s), 2.28 (3H, s), 2.12 (3H, s), 1.57 (9H , s); MS (ESI ⁺ ) = 464.36 (M+H) ⁺ .

2-(2′-Methyl-biphenyl-4-yl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1- Ketone : 4-(1-tert-butyl-5-methyl-1H-pyrazol-3-ylamino)-2-(2'-methyl-biphenyl-4-yl)-2H-2, 3-Naphthyridine-1-one was deprotected with formic acid as described in Method O to afford the title compound (0.036 g, 83% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.29 (1H, s), 8.52 (1H, d), 8.40 (1H, d), 8.17 (1H, s), 7.97 (1H, t), 7.93 ( 1H,t), 7.82(2H,d), 7.48(2H,d), 7.30(4H,m), 6.29(1H,s), 2.33(3H,s), 2.20(3H,s); MS(ESI ⁺ )＝408.16(M+H) ⁺ .

Method R - Bromination in pure _POBr3

Example R-1: 4-(5-methyl-1H-pyrazol-3-ylamino)-2-(3-trifluoromethyl-phenyl)-2H-2,3-naphthyridine- 1-keto

4-Hydroxy-2-(3-trifluoromethylphenyl)-2H-2,3-naphthyridine-1-one : 4-hydroxy-2-(3-trifluoromethylphenyl)-2H -2,3-Naphthyridine-1-one was prepared from 3-trifluoromethylphenylhydrazine as described in Method B. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.95 (1H, s), 8.31 (1H, d), 7.91-8.10 (5H, m), 7.74 (2H, d); MS (ESI ⁺ ) = 307.14 (M+H) ⁺ .

4-Bromo-2-(3-trifluoromethylphenyl)-2H-2,3-naphthyridine-1-one: 4-hydroxyl-2-(3-trifluoromethylphenyl) - 2H-2,3-naphthyridine-1-one (0.50 g, 1.6 mmol) and phosphorus oxybromide (1.9 g, 6.5 mmol) were stirred at 150° C. for 2 hours. After cooling to room temperature, _H2O (100ml) was added. The precipitated solid was collected by filtration and washed with _H2O . The solid was dried in vacuo to give the title compound (0.4 g, 66% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.39 (1H, d), 7.95-8.12 (5H, m), 7.79-7.99 (2H, m); MS (ESI ⁺ ) = 370.98 (M+H) ⁺ .

This material was then used in the Buchwald reaction as described in Method A to give the corresponding 4-(5-methyl-1H-pyrazol-3-ylamino)-2-(3-trifluoromethyl- Phenyl)-2H-2,3-phthalazin-1-one (Example R-1).

4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(3-trifluoromethyl-phenyl)-2H-2,3-naphthyridine- 1-one: Yield (0.078g, 19%); ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.95 (1H, s), 9.38 (1H, s), 8.53 (1H, d), 8.41 (1H, d), 8.20 (2H, s), 7.98 (2H, t), 7.94 (2H, t), 7.69-7.74 (2H, m), 6.27 (1H, s), 2.19 (3H, s).

Using the experimental conditions reported above (Method R and the Buchwald reaction as described in Method A) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) R-2 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-phenoxy-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.95(1H,s), 9.26(1H,s), 8.50(1H,d), 7.98(1H,d), 7.88-7.99(2H,m), 7.73(2H,d ), 7.44(2H,t), 7.19(1H,t), 7.11(4H,d), 6.24(1H,s), 2.19(3H,s) 410.17 R-3 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-naphthalen-2-yl-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.96(1H, s), 9.33(1H, s), 8.55(1H, d), 8.41(1H, d), 8.30(1H, s), 7.87-8.05(6H, m ), 7.58(2H, m), 6.31(1H, s), 2.17(3H, s) 368.3 R-4 2-(2-Chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.98(1H,s), 9.27(1H,s), 8.51(1H,d), 8.33(1H,d), 7.99(1H,t), 7.91(1H,t), 7.61-7.68 (2H, m), 7.50-7.53 (2H, m), 6.06 (1H, s), 2.13 (3H, s) 352.3

Method S

Example S-1: N-methyl-4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2 -yl]-benzamide

4-(4-Bromo-1-oxo-1H-2,3-phthalazin-2-yl)benzoic acid : The title compound was obtained from the appropriate starting material using the experimental conditions reported above (Method R). Yield (0.65 g, 33%); ¹ H-NMR: (400 MHz, D ₆ -DMSO) 13.10 (1H, s), 8.39 (1H, d), 8.01-8.12 (5H, m), 7.80 (2H, d); MS (ESI ⁺ ) = 345.13 (M + H) ⁺ .

4-(4-Bromo-1-oxo-1H-2,3-naphthyridine-2-yl)-N-methyl-benzamide : At room temperature, 4-(4-bromo -1-oxo-1H-2,3-phthalazin-2-yl)benzoic acid (0.15g, 0.43mmol) and 1,1'-carbonyldiimidazole (0.10g, 0.65mmol) were dissolved in DMF ( 10ml). Methylamine (0.33 ml of a 2M solution in THF, 0.65 mmol) was added and stirring was continued for 4 hours. The solvent was evaporated under reduced pressure, diluted with DCM, extracted with saturated aqueous NaHCO ₃ and the solvent was evaporated in vacuo to give the title compound (0.12 g, 77% yield) ¹ H-NMR: (400 MHz, D ₆ -DMSO) 8.55(1H,d), 8.38(1H,d), 8.10(1H,t), 8.03(2H,d), 8.02(2H,d), 7.73(2H,d), 2.82(3H,d).

This material was then used in the Buchwald reaction as described in Method A to give the corresponding N-methyl-4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1 -Oxo-1H-2,3-naphthyridine-2-yl]-benzamide (Example S-1).

N-methyl-4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2- yl]-benzo Amide : Yield (0.005 g, 10%); ¹ H-NMR: (400 MHz, D ₆ -DMSO) 11.95 (1H, s), 9.33 (1H, s), 8.52 (2H, d), 8.50 (1H, d), 7.84-8.03 (6H, m), 6.27 (1H, s), 2.74 (3H, s), 2.20 (3H, s).

Method T

Example T-1: N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl ]-phenyl}-acetamide

2-(4-amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-phthalazin-1-one (C -2, 0.050g, 0.15mmol) was dissolved in pyridine (1ml). Acetyl chloride (0.024ml, 0.33mmol) was added and after stirring was continued at 0°C for 30 minutes the mixture was allowed to warm to room temperature. After stirring at room temperature for 2 hours the solvent was evaporated. The residue was diluted in MeOH (1 ml) and treated with concentrated _NH3 (1 ml). The title compound was obtained after stirring at room temperature for 24 hours and the solvent was evaporated in vacuo (0.016 g, 29%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.93(1H,s), 10.08(1H,s), 9.26(1H,s), 8.49(1H,d), 8.36(1H,d), 7.88- 7.98(2H, m), 7.61-7.69(4H, m), 6.24(1H, s), 2.19(3H, s), 2.08(3H, s); MS(API ⁺ )=375(M+H) ⁺ .

Using the experimental conditions reported above and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) T-2 2-methoxy-N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl ]-phenyl}-acetamide (400MHz, D ₆ -DMSO) 11.93(1H, s), 9.90(1H, s), 9.26(1H, s), 8.50(1H, d), 8.36(1H, d), 7.88-7.98(2H, m ), 7.77(2H,d), 7.64(2H,d), 6.24(1H,s), 4.04(2H,s), 3.41(3H,s), 2.19(3H,s) 405.35 T-3 2,2-Dimethyl-N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2 -yl]-phenyl}-propionamide (400MHz, D ₆ -DMSO)9.33(1H,s), 9.27(1H,s), 8.55(1H,d), 8.36(1H,d), 7.87-8.01(2H,m), 7.75(2H,d ), 7.63 (2H, d), 6.28 (1H, s), 2.21 (3H, s), 1.26 (9H, s) 417.4 T-4 N-{4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl}- benzamide (400MHz, D ₆ -DMSO) 10.40(1H, d), 9.28(1H, s), 8.53(1H, d), 8.37(1H, t), 7.30-8.10(12H, m), 6.27(1H, s ), 2.21(3H,s) 437.55 T-5 N-{4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl}- Methanesulfonamide (400MHz, D ₆ -DMSO)9.85(1H,d), 9.25(1H,s), 8.50(1H,d), 8.36(1H,d), 7.92-7.99(2H,m), 7.68(2H,d ), 7.31(2H, d), 6.23(1H, s), 3.07(3H, s), 2.19(3H, s) 411.19

Method U

Example U-1: 4-(5-methyl-1H-pyrazol-3-ylamino)-2-(4-phenylamino-phenyl)-2H-2,3-naphthyridine-1 -ketone

Under argon, 2-(4-chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-phthalazin-1-one (B-1, 0.10g, 0.28mmol), aniline (0.034g, 0.37mmol), NaOtBu (0.041g, 0.43mmol), tris-(dibenzylideneacetone)-dipalladium (0.026g, 0.028mmol) and 2-(Di-tert-butylphosphine)-biphenyl (0.017 g, 0.057 mmol) was heated to 100° C. for 17 hours and then allowed to cool to room temperature. The solvent was evaporated in vacuo, the residue was diluted with _H2O (50ml) and the resulting solid was collected by filtration. The crude product was purified by column chromatography on silica gel with DCM:MeOH (20:1) to give the title compound (0.002 g, 2% yield) as a white solid (Example U-1). ¹ H-NMR: (400MHz, D ₆ -DMSO) 12.0 (1H, s), 9.23 (1H, s), 8.49 (1H, d), 8.33-8.37 (2H, m), 7.88-7.97 (2H, m ), 7.54(2H, d), 7.28(2H, t), 7.15(4H, m), 6.86(1H, t), 6.25(1H, s), 2.19(3H, s); MS(API ⁺ )= 409.0(M+H) ⁺ .

Using the experimental conditions reported above (Method U) and suitable starting materials, the following derivatives were prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) U-2 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-morpholin-4-yl-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO)9.21(1H,s), 8.49(1H,d), 8.35(1H,d), 7.82-7.96(2H,m), 7.55(2H,d), 7.04(2H,d ), 6.26(1H, s), 3.77(4H, t), 3.18(4H, t), 2.19(3H, s) 403.54 U-3 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-pyrrolidin-1-yl-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 9.21(1H,s), 8.47(1H,d), 8.33(1H,d), 7.82-7.99(2H,m), 7.45(2H,d), 6.61(2H,d ), 6.21(1H, s), 3.28(4H, s), 2.17(3H, s), 1.98(4H, s) 387.54

Method V

Example V-1: 4-(5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-2,3-diazepine Naphthalene-1-one

4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-chloro-phenyl)-2H-2,3-naphthyridine-1- one : At 100°C, under nitrogen, 200 mg of 4-bromo-2-(4-chloro-phenyl)-2H-2,3-phthalazin-1-one in 2 ml of anhydrous dioxane (prepared as described in Method R), 91 mg 1-tert-butyl-3-methyl-1H-pyrazol-5-ylamine, 310 mg cesium carbonate, 21 mg 4,5-bis(diphenylphosphine)- 9,9-Dimethylxanthene and 16.4 mg of tris-(dibenzylideneacetone)-dipalladium were stirred for 18 hours. The solvent was removed under vacuum and the residue was stirred with 50 ml of water. The crude product is isolated by filtration, washed with water and purified by chromatography on silica gel, eluting sequentially with heptane, DCM and finally DCM/MeOH 60:1. Yield: 180 mg (74%) of the title product.

4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-2,3- diazepine Naphthalene-1-one : Under argon, 4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-chlorophenyl)-2H-2 , 3-naphthyridine-1-one (0.10 g, 0.25 mmol), piperidine (0.025 g, 0.29 mmol), NaOtBu (0.033 g, 0.34 mmol), tris-(dibenzylideneacetone)-dipalladium (0.06 g, 0.008 mmol) and 2-(di-tert-butylphosphine)-biphenyl (0.004 g, 0.014 mmol) were heated to 100° C. for 19 hours and then allowed to cool to room temperature. The solvent was evaporated in vacuo, the residue was diluted in _H2O (30ml) and the resulting solid was collected by filtration. The crude product was purified by preparative HPLC to afford the title compound (0.014 g, 13% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.35 (1H, d), overlap 8.34 (1H, s), 8.29 (1H, d), 8.01 (1H, t), 7.92 (1H, t), 7.31 (2H, d), 6.92 (2H, d), 5.94 (1H, s), 3.16 (4H, m), 1.61 (4H, m), 1.55 (9H, s), overlap 1.54 (2H, m); MS (ESI ⁺ )＝457.16(M+H) ⁺

4-(5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-2,3-naphthyridine-1-one:

4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-2,3-diazo Xinaphthin-1-one (0.012g, 0.026mmol) was dissolved in formic acid (1ml) and heated at 95°C for 4 hours. After evaporation of formic acid, the obtained crude product was dissolved in DCM. Extraction with saturated aqueous NaHCO ₃ , combined organic phases, evaporation of solvent in vacuo and purification by chromatography on silica gel with DCM:MeOH (20:1 ) gave the title compound (0.006 g, 57%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.81 (1H, s), 9.21 (1H, s), 8.48 (1H, d), 8.35 (1H, d), 7.87-7.96 (2H, m), MS (ESI ⁺ )＝401.29(M+H) ⁺ .

Method W - Buchwald coupling with Boc-protected aminopyrazoles

Example W-1: 2-(2-chloro-4-trifluoromethyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-di Aziridine-1-one

2-(2-Chloro-4-trifluoromethyl-phenyl)-2,3-dihydro-2,3-naphthyridine-1,4-dione : treated with 347 mg of sodium ethoxide in 80 ml of 1.74 g of 2-(2-chloro-4-trifluoromethyl-phenylamino)-isoindole-1,3-dione (prepared from 2-chloro-4 -trifluoromethyl-phenylhydrazine) and the mixture was stirred at 85C for 2 hours. After cooling, the mixture was evaporated and dissolved in water. The precipitate was filtered off and washed several times with water. The combined filtrates were acidified by the addition of concentrated hydrochloric acid, followed by precipitation of the product. It was isolated by filtration and purified by chromatography on silica gel eluting with a gradient of heptane/EtOAc (50:50) to pure EtOAc. Yield 250 mg (14%)

3-Amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester : Add NaH (95%, 0.57g, 22.7mmol) slowly to 3-amino-5-methylpyrazole (2.0g, 20.6mmol ) in THF (40ml) at 0°C. After 30 minutes _Boc2O (4.94 g, 22.7 mmol) was added and the mixture was allowed to warm to room temperature. After stirring at room temperature for 2 h, the mixture was poured into saturated aqueous NaHCO ₃ . The aqueous phase was extracted with _CHCl3 . The combined organic phases were dried _{over Na2SO4} . The solvent was removed in vacuo to give a crude mixture of the title compound and its tert-butyl 2-carboxylate isomer, which were separated by chromatography on silica gel in EtOAc/heptane 2:1. Yield 2.4g, 59%. ¹ H-NMR: (400MHz, D ₆ -DMSO) 5.60 (1H, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI ⁺ )＝198.26(M+H) ⁺ .

Typical procedure for the Buchwald reaction with tert-butoxycarbonyl-protected pyrazoles

2-(2-Chloro-4-trifluoromethyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3- naphthyridine - 1- Ketone : 4-Bromo-2-(2-chloro-4-trifluoromethyl-phenyl)-2H-2,3-naphthyridine- 1-Kone (obtained from 2,3-naphthyridine-1,4-dione above by bromination with POBr ₃ in a manner analogous to Method R as reported above) (0.15 g, 0.37 mmol), 3 -Amino-5- _methyl -pyrazole-1-carboxylic acid tert-butyl ester (0.080g, 0.41mmol), _Cs2CO3 (0.033g, 0.34mmol), tris-(dibenzylideneacetone)-dipalladium (0.017g, 0.019mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.022g, 0.037mmol) were heated to 100°C for 18 hours, then allowed to cool to room temperature . _H2O was added and the solvent was evaporated in vacuo. The resulting solid was collected by filtration. The crude product was purified by preparative HPLC to afford the title compound (0.069 g, 44% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.92 (1H, s), 9.34 (1H, s), 8.54 (1H, d), 8.35 (1H, d), 8.14 (1H, s), 8.01 ( 1H, t), 7.92(3H, m), 6.06(1H, s), 2.14(3H, s); MS(ESI ⁺ )=420.23(M+H) ⁺ .

Similarly, 4-bromo-2-(4-trifluoromethoxy-phenyl)-2H-2,3-naphthyridine-1-one, 4-bromo-2-(4-nitro Phenyl)-2H-2,3-naphthyridine-1-one and 4-bromo-2-(4-cyclohexyl-phenyl)-2H-2,3-naphthyridine-1-one (obtained from the corresponding phenylhydrazine following Method R) coupled with tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate to give:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) W-2 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-trifluoromethoxy-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.97(1H,s), 9.30(1H,s), 8.53(1H,d), 8.38(1H,d), 8.01-7.88(m) and 7.90(d, common 4H) , 7.51 (2H, d), 6.25 (1H, s), 2.20 (3H, s). 402.21 W-3 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(4-nitro-phenyl)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 12.05(1H,s), 9.42(1H,s), 8.54(1H,d), 8.36-8.42(3H,m), 8.15-8.17(2H,m), 7.91-8.02 (2H, m), 6.30 (1H, s), 2.23 (3H, s) 363.3 W-4 2-(4-cyclohexyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine (400MHz, D ₆ -DMSO), 9.22(1H, s), 8.50(1H, d), 8.35(1H, d), 8.03-7.84(2H, m), 7.62(2H, d), 7.35(2H, d), 6.24(1H, s), 400.20

Xinaphthin-1-one 2.59 (1H, m), 2.19 (3H, s), 1.90-1.78 (4H, m), 1.78-1.61 (1H, m), 1.55-1.20 (5H, m).

Method X - Buchwald coupling with aminopyrazole and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xanthphos)

Example X-1: 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-pyridin-4-yl-2H-2,3-naphthyridine-1-one

Under nitrogen, 4-bromo-2-pyridin-4-yl-2H-2,3-phthalazin-1-one (obtained from appropriate starting materials in a manner analogous to Method R as reported above) (0.20g, 0.66mmol), 3-amino-5-methyl-pyrazole (0.093g, 0.93mmol), Cs ₂ CO ₃ (0.30g, 0.93mmol), three-(dibenzylideneacetone)-di Palladium (0.030 g, 0.033 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xanthphos) (0.039 g, 0.066 mmol) were heated to 100° C. for 20 hours, and then Allow to cool to room temperature. _H2O was added and the solvent was evaporated in vacuo. The resulting solid was collected by filtration. The crude product was purified by chromatography on silica gel to afford the title compound (0.015 g, 7% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 12.0 (1H, s), 9.38 (1H, s), 8.67 (2H, d), 8.53 (1H, d), 8.40 (1H, d), 7.91- 8.02 (4H, m), 6.31 (1H, s), 2.24 (3H, s); MS (ESI ⁺ ) = 319.2 (M + H) ⁺ .

Example X-2: 2-(3-tert-butyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1 -ketone

Under nitrogen, 4-bromo-2-(3-tert-butylphenyl)-2H-2,3-phthalazin-1-one (obtained in a similar manner to method R as reported above from a suitable starting material) (0.10g, 0.28mmol), 3-amino-5-methyl-pyrazole (0.038g, 0.39mmol), Cs ₂ CO ₃ (0.13g, 0.39mmol), tris-(dibenzylidene- Acetone)-dipalladium (0.013g, 0.014mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.016g, 0.028mmol) were heated to 100°C for 10 hours and then Allow to cool to room temperature. _H2O was added and the solvent was evaporated in vacuo. The resulting solid was collected by filtration. The crude product was purified by chromatography on silica gel to afford the title compound (0.020 g, 19% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.32 (1H, s), 8.50 (1H, d), 8.38 (1H, d), 7.95 (1H, t), 7.90 (1H, t), 7.78 ( 1H, s), 7.63 (1H, d), 7.37-7.40 (2H, m), 6.38 (1H, s), 2.18 (3H, s), 1.22 (9H, s); MS (ESI ⁺ ) = 374.27 ( M+H) ⁺ .

Similar to the example described above, 4-bromo-2-(4-tert-butyl-phenyl)-2H-2,3-phthalazin-1-one (obtained as method R) was mixed with a suitable Amino-pyrazole coupling to give:

Example number. system name ¹ H-NMR MS (API+, M+H ⁺ ) X-3 2-(4-tert-butyl-phenyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO) 11.95(1H,s), 9.23(1H,s), 8.50(1H,d), 8.37(1H,d), 8.03-7.88(2H,m), 7.66(2H,d ), 7.50 (2H, d), 6.21 (1H, s), 1.88 (1H, m), 1.35 (9H, s), 0.91 (2H, m), 0.64 (2H, m). 400.21 X-4 2-(4-tert-butyl-phenyl)-4-(1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (400MHz, D ₆ -DMSO), 12.29(1H,s), 9.39(1H,s), 8.54(1H,d), 8.38(1H,d), 7.96(1H,m), 7.91(1H,m) , 7.64 (3H, m), 7.51 (2H, d), 6.53 (1H, s), 1.35 (9H, s). 360.19

Method Y

Example Y-1: N-ethyl-N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-diazepine Naphthalene-2-yl]-phenyl}-acetamide

2-(4-Amino-phenyl)-4-bromo-2H-2,3-naphthyridine-1-one : At room temperature, 4-bromo-2-(4-nitro-benzene 2H-2,3-phthalazin-1-one (see Method B) (1.0 g, 2.9 mmol) and PtO ₂ (0.13 g, 0.58 mmol) were dissolved in EtOAc (40 ml). The mixture was hydrogenated at ambient pressure for 2 hours, after which the catalyst was filtered off to give the title compound (0.61 g, 67% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.34 (1H, d), 8.07 (1H, t), 7.99 (2H, t), 7.18 (2H, d), 6.63 (2H, d), 5.35 ( 2H, s); MS (ESI ⁺ ) = 318.42 (M+H) ⁺ .

N-[4-(4-Bromo-1-oxo-1H-2,3-phthalazin-2-yl)-phenyl]acetamide : Acetyl chloride (0.15g, 1.90mmol) was dissolved at room temperature A stirred solution of 2-(4-amino-phenyl)-4-bromo-2H-2,3-phthalazin-1-one (0.30 g, 0.95 mmol) in pyridine (3 ml) was added. Stirring was continued for 12 hours, after which the solvent was evaporated in vacuo. The resulting crude product was dissolved in _H2O and the title compound was collected by filtration (0.22 g, 65% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 10.16 (1H, s), 8.37 (1H, d), 8.08 (1H, t), 8.00-8.03 (2H, m), 7.72 (2H, d), 7.52 (2H, d), 2.05 (3H, s); MS (ESI ⁺ ) = 358.15 (M + H) ⁺ .

N-[4-(4-Bromo-1-oxo-1H-2,3-phthalazin-2-yl)-phenyl]-N-ethyl-acetamide : at room temperature, NaH (95%, 0.005g, 0.21mmol) was slowly added N-[4-(4-bromo-1-oxo-1H-2,3-phthalazin-2-yl)-phenyl]acetamide ( 0.070 g, 0.20 mmol) in DMF (2 ml). Stirring was continued for 1 hour before ethyl iodide (0.046 g, 0.29 mmol) was added. Stirring was continued for 12 hours, after which the solvent was evaporated in vacuo. The resulting crude product was purified by chromatography on silica gel with heptane:EtOAc (3:1 to 1:1) to afford the title compound (0.010 g, 14% yield). MS (ESI ⁺ ) = 388.22 (M + H) ⁺ .

N-ethyl-N-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine- 2-yl] -Phenyl}-acetamide : Under nitrogen, N-[4-(4-bromo-1-oxo-1H-2,3-naphthyridine-2-yl)-phenyl]-N -Ethyl-acetamide (0.10g, 0.027mmol), 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.006g, 0.03mmol), Cs ₂ CO ₃ (0.01g, 0.03 mmol), tris-(dibenzylideneacetone)-dipalladium (0.001g, 0.001mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.002g, 0.003mmol ) to 100°C for 18 hours and then allowed to cool to room temperature. _H2O was added and the solvent was evaporated in vacuo. Purification by chromatography afforded the title compound (0.003 g, 23% yield). ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.28(1H, s), 8.51(1H, d), 8.38(1H, d), 7.99(1H, t), 7.91(1H, t), 7.87( 2H, d), 7.41 (2H, d), 6.25 (1H, s), 3.69 (2H, q), 2.20 (3H, s), 1.81 (3H, s), 1.07 (3H, t); MS (ESI ⁺ )＝403.34(M+H) ⁺ .

Analogously to Example Y-1, 2-(4-amino-phenyl)-4-bromo-2H-2,3-phthalazin-1-one was acylated with the appropriate chloroformate to give the corresponding of carbamate. These were used directly for coupling with Boc-protected amino-pyrazole under Buchwald conditions as described for Y-1, or first alkylated and then used for Buchwald coupling as described for Y-1 . Thus, the following analogues are obtained:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) Y-2 {4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl}-carbamic acid ethyl ester (400MHz, D ₆ -DMSO) 9.76(1H, s), 9.25(1H, s), 8.49(1H, d), 8.36(1H, d), 7.97(1H, t), 7.89(1H, t), 7.58 (4H, dd), 6.23 (1H, s), 4.16 (2H, q), 2.19 (3H, s), 1.27 (3H, t). 405.36 Y-3 Methyl-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl} - Urethane (400MHz, D ₆ -DMSO) 11.95(1H,s), 9.22(1H,s), 8.50(1H,d), 8.34(1H,d), 7.98-7.91(2H,m), 7.73(2H,d ), 7.43 (2H, d), 6.23 (1H, s), 4.12 (2H, q), 2.20 (3H, s), 1.21 (3H, t). 419.30 Y-4 Methyl-{4-[4-(5-methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl} - Isopropyl carbamate (400MHz, D ₆ -DMSO)9.27(1H,s), 8.52(1H,d), 8.37(1H,d), 7.98-7.90(2H,m), 7.71(2H,d), 7.42(2H,d ), 6.28 (1H, s), 4.86 (1H, m), 2.20 (3H, s), 1.21 (6H, d). 433.33 Y-5 {4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-1-oxo-1H-2,3-naphthyridine-2-yl]-phenyl}-carbamic acid Isopropyl ester (400MHz, D ₆ -DMSO) 11.92(1H, br s), 9.70(1H, s), 9.26(1H, s), 8.49(1H, d), 8.35(1H, d), 8.01-7.85(2H, m), 7.59 (4H, dd), 6.23 (1H, s), 4.93 (1H, hep), 2.18 (3H, s), 1.28 (6H, d). 419.26

Method Z:

Following analogous procedures as described under Method ZB, using appropriate starting materials, the following examples can be prepared:

Example number system name ¹ H-NMR MS (API+, M+H ⁺ ) Z-1 6-Amino-4-(5-methyl-1H-pyrazol-3-ylamino)-2-phenyl-2H-2,3-naphthyridine-1-one

Method ZA - Sulfanyl-substituted 2-phenylnaphthyridinones from 2-(iodophenyl)naphthyridinones

Example ZA-1: 2-[4-(2-Methyl-propane-2-sulfonyl)-phenyl]-4-(5-methyl-1H-pyrazol-3-ylamino)-2H- 2,3-Naphthyridine-1-one

2-(4-tert-butylthio-phenyl)-2,3-dihydro-2,3-naphthyridine-1,4-dione : 4-hydroxy-2-(4-iodophenyl )-2H-2,3-naphthyridine-1-one (see Method Q) (0.30 g, 0.8 mmol), sodium 2-methyl-propane-2-thiol (0.094 g, 0.8 mmol), CuI (0.011 g, 0.06 mmol) and ethylene glycol (0.10 g, 1.6 mmol) were dissolved in N-methyl-pyrrolidone (NMP) (0.5 ml) and heated to 150°C. After stirring was continued at this temperature for 4 days the mixture was allowed to warm to room temperature. _H2O (50ml) was added and the precipitated solid was collected by filtration. The title mixture was obtained after purification of the crude product by chromatography on silica gel with DCM (0.21 g, 78%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 12.35 (1H, s), 8.73 (1H, d), 8.33-8.41 (3H, m), 8.14 (2H, d), 8.01 (2H, d), 1.70 (9H, s); MS (ESI ⁺ ) = 327.14 (M + H) ⁺ .

2-[4-(2-methyl-propane-2-sulfonyl)-phenyl]-2,3-dihydro-2,3-naphthyridine-1,4-dione: 2-( 4-tert-butylthio-phenyl)-2,3-dihydro-2,3-naphthyridine-1,4-dione (0.20g, 0.61mmol) and MCPBA (0.28g, 1.2mmol) in Stir in DCM (3ml) at room temperature for 4 hours. The title compound (0.21 g, 98%) was obtained after evaporation of the solvent in vacuo and subsequent purification of the crude product by chromatography on silica gel with heptane:DCM (1:1 until 0:1). ¹ H-NMR: (400MHz, D ₆ -DMSO) 13.30 (1H, s), 8.34 (1H, d), 7.85-8.12 (3H, m), 7.72 (2H, d), 7.55 (2H, t), 1.28 (9H, s); MS (ESI ⁺ ) = 359.16 (M + H) ⁺ .

4-bromo-2-[4-(2-methyl-propane-2-sulfonyl)-phenyl]-2H-2,3-naphthyridine-1-one : 2-[4-( 2-Methyl-propane-2-sulfonyl)-phenyl]-2,3-dihydro-2,3-naphthalene-1,4-dione (0.20g, 0.56mmol) and tribromooxidized Phosphorus (0.48 g, 1.7 mmol) was stirred at 150°C for 1 hour. After cooling to room temperature _H2O (50ml) was added. Extraction with DCM, drying of the combined organic phases over _Na2SO4 , evaporation of the solvent and purification of the crude product by preparative HPLC yielded the desired compound (0.06 g, 18% ₎ . ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.41 (1H, d), 8.07 (1H, d), 8.03-8.10 (4H, m), 7.80 (2H, d), 1.30 (9H, s); MS(API ⁺ )＝423.0(M+H) ⁺ .

This material was then used in the Buchwald reaction as described in Method A to give the corresponding 2-[4-(2-methyl-propane-2-sulfonyl)-phenyl]-4-(5- Methyl-1H-pyrazol-3-ylamino)-2H-2,3-phthalazin-1-one (Example ZA-1).

2-[4-(2-Methyl-propane-2-sulfonyl)-phenyl]-4-(5-methyl-1H-pyrazol-3- ylamino )-2H-2,3-di Aziridine-1-one : yield (0.003 g, 8%); ¹ H-NMR: (400 MHz, D ₆ -DMSO) 9.40 (1H, s), 8.52 (1H, d), 8.39 (1H, d ), 8.13 (2H, d), 7.99 (1H, t), 7.92 (2H, d), overlapping 7.91 (1H, t), 6.29 (1H, s), 1.30 (9H, s); MS (API ⁺ ) ＝438.3(M+H) ⁺ .

Example ZA-2: 2-(4-Benzenesulfinyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine- 1-keto

2-(4-Phenylthio-phenyl)-2,3-dihydro-2,3-naphthyridine-1,4-dione : Under argon, 4-hydroxy-2-(4 -iodophenyl)-2H-2,3-phthalazin-1-one (see method Q) (0.20g, 0.55mmol), thiophenol (0.061g, 0.55mmol), CuI (0.006g, 0.03 mmol) and ethylene glycol (0.070 g, 1.1 mmol) were dissolved in N-methyl-pyrrolidone (NMP) (1 ml) and heated to 90°C. Stirring was continued at this temperature for 26 hours, after which time the mixture was allowed to warm to room temperature. _H2O (50ml) was added and the resulting solution was extracted with DCM. The title compound was obtained after purification of the crude product by chromatography on silica gel with DCM (0.10 g, 54%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.91 (1H, s), 8.30 (1H, s), 7.91-8.06 (3H, m), 7.69 (2H, d), 7.34-7.45 (7H, m ); MS (ESI ⁺ ) = 347.26 (M + H) ⁺ .

4-Bromo-2-(4-phenylthio-phenyl)-2H-2,3-naphthyridine-1-one : 2-(4-phenylthio-phenyl)-2,3 - Dihydro-2,3-naphthyridine-1,4-dione (0.10 g, 0.29 mmol) and phosphorus oxybromide (0.33 g, 12 mmol) were stirred at 150° C. for 40 minutes. After cooling to room temperature _H2O (50ml) was added. Extraction with DCM, drying of the combined organic phases over _Na2SO4 , evaporation of the solvent and purification of the crude product by chromatography on silica gel with heptane:DCM (2:1 to 0: ₁ ) gave the desired compound (0.10 g, 86%). ¹ H-NMR: (400MHz, D ₆ -DMSO) 8.36 (1H, d), 8.11 (1H, d), 8.00 (2H, m), 7.65 (2H, d), 7.44 (7H, m); MS ( ESI ⁺ )＝411.2(M+H) ⁺

2-(4-Benzenesulfinyl-phenyl)-4-bromo-2H-2,3-naphthyridine-1-one: 4-bromo-2-(4-phenylsulfanyl-benzene (1)-2H-2,3-naphthyridine-1-one (0.095 g, 0.23 mmol) and MCPBA (0.052 g, 0.23 mmol) were stirred in DCM (1 ml) at room temperature for 1 hour. The title compound was obtained after evaporation of the solvent in vacuo and subsequent purification of the crude product by chromatography on silica gel with heptane:DCM (1:1 until 0:1). ¹ H-NMR: (400MHz, CDCl ₃ ) 8.49 (1H, d), 7.80-7.99 (5H, m), 7.76 (2H, d), 7.69 (2H, d), 7.48 (3H, m); MS ( ESI ⁺ )＝427.22(M+H) ⁺ .

This material was then used in the Buchwald reaction as described in Method A to give the corresponding 2-(4-phenylsulfinyl-phenyl)-4-(5-methyl-1H-pyrazole-3 -ylamino)-2H-2,3-naphthyridine-1-one (Example ZA-2).

2-(4-Benzenesulfinyl-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one : yield (0.003g, 9%); ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.31 (1H, s), 8.50 (1H, d), 8.36 (1H, d), 7.89-8.00 (4H, m) , 7.83(2H, d), 7.80(2H, d), 7.54(3H, m), 6.22(1H, s), 2.20(3H, s); MS(ESI ⁺ )=440.33(MH) ⁺ .

Method ZB: 6- and 7-substituted 2-phenyl-4-pyrazolylamino-2,3-phthalazinones

Example ZB-1: N-[3-(4-tert-butyl-phenyl)-1-(5-methyl-2H-pyrazol-3-ylamino)-4-oxo-3,4- Dihydro-2,3-naphthyridine-6-yl]-carboxamide

4-bromo-2-(4-tert-butyl-phenyl)-6-nitro-2H-2,3-phthalazin-1-one and 4-bromo- 2-(4-tert-butyl Base-phenyl)-7-nitro-2H-2,3-naphthyridine-1-one and 4,6-dibromo-2-(4-tert-butyl -phenyl)-2H-2 , 3-naphthyridine-1-one : 4-nitrophthalic anhydride and 4-tert-butylphenylhydrazine were reacted in a similar manner to Method B to give 2-(4-tert-butyl- Phenyl)-6-nitro-2,3-dihydro-2,3-naphthyridine-1,4-dione and 2-(4-tert-butyl-phenyl)-7-nitro- 1:1 mixture of 2,3-dihydro-2,3-naphthyridine-1,4-dione. To 1.60 g of this mixture, 6.47 g of phosphorus oxybromide was added and heated to 150C with stirring. After 1 hour, HPLC showed complete conversion, and the mixture was cooled to room temperature, diluted with 100 ml of water and stirred for 15 minutes. The crude product was isolated by filtration and purified by chromatography on silica gel, eluting first with heptane and then with heptane/EtOAc 1:1. The first eluting material was 4,6-dibromo-2-(4-tert-butyl-phenyl)-2H-2,3-phthalazin-1-one (121 mg), followed by 4-bromo Substituent-2-(4-tert-butyl-phenyl)-6-nitro-2H-2,3-naphthyridine-1-one and 4-bromo-2-(4-tert-butyl-benzene 1:1 mixture (720 mg) of -7-nitro-2H-2,3-naphthyridine-1-one.

6-nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl- phenyl )-2H-2,3-di Azanaphthalen-1-one and 7-nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3- ylamino )-2-(4-tert-butyl-phenyl )-2H-2,3-naphthyridine-1-one : 4.56g of 4-bromo-2-(4-tert-butyl-phenyl)-6-nitro- 2H-2,3-naphthyridine-1-one and 4-bromo-2-(4-tert-butyl-phenyl)-7-nitro-2H-2,3-naphthyridine-1 - A 1:1 mixture of ketone in 45 ml dry dioxane with 2.605 g 1-(tert-butyl)-3-methyl-1H-pyrazol-5-ylamine, 5.526 g cesium carbonate, 311 mg tris-( Dibenzylideneacetone)-dipalladium and 393 mg of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene were reacted. After 2 hours, HPLC showed complete conversion and the mixture was cooled to room temperature, diluted with 150 ml DCM, and washed twice with diluted HCl. The organic phase is dried and evaporated, and the residue is chromatographed on silica gel, eluting first with heptane and then with heptane/EtOAc 8:2. The first eluted product was the 6-nitro isomer (1.82 g), followed by the 7-nitro isomer (2.05 g).

7-Amino-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl- phenyl )-2H-2,3-diazepine Xanaphthin-1-one : 2.00 g of 7-nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl Hydrogenation on palladium on carbon was carried out in MeOH/THF 1:1. After the reaction was complete, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 50 ml DCM and extracted three times with a 3:1 mixture of water/cone HCl. The combined aqueous phases were adjusted to pH 8 by addition of sodium bicarbonate and extracted with DCM. Removal of solvent yielded 1.25 g of the title product.

N-[3-(4-tert-butyl-phenyl)-1-(5-methyl-2H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro- 2,3 -Naphthyridine-6-yl]-carboxamide : 15 mg of the above tert-butyl-protected pyrazole were heated to 90° C. for 6 hours in 1 ml of formic acid. Excess formic acid was removed under vacuum and the residue was dissolved in DCM and washed with sodium bicarbonate solution. Evaporation with DCM yielded 12 mg of the title product. ¹ H-NMR: (400 MHz, D ₆ -DMSO) 12.00 (1H, s), 10.77 (1H, s), 9.17 (1H, s), 8.61 (1H, s), 8.50 (2H, m), 8.10 ( 1H, m), 7.63 (2H, d), 7.51 (2H, d), 6.22 (1H, s), 2.19 (3H, s), 1.35 (9H, s); MS (ESI ⁺ ) = 417.25 (M+ H) ⁺ .

Example ZB-2: 7-amino-2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-diazepine Xinaphthin-1-one

9 mg of N-[3-(4-tert-butyl-phenyl)-1-(5-methyl-2H-pyrazol-3-yl) in a mixture of 0,5 ml MeOH and 0,5 ml concentrated HCl Amino)-4-oxo-3,4-dihydro-2,3-phthalazin-6-yl]-carboxamide (ZB-1) was stirred at 50°C for 2 hours. The mixture was evaporated under vacuum and the residue was dissolved in DCM. The DCM solution was washed with sodium bicarbonate solution and evaporated to give 4 mg of the title product. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.8 (1H, br s), 8.81 (1H, s), 8.02 (1H, d), 7.52 (2H, d), 7.40 (2H, d), 7.34 (1H, d), 6.99(1H, dd), 6.10(br s, 2H), 2.10(3H, s), 1.27(9H, s); MS(ESI ⁺ )=389.21(M+H) ⁺ .

Example ZB-3: 2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-7-nitro-2H-2,3-di Aziridine-1-one

15 mg of 7-nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-2,3 -Naphthyridine-1-one (preparation see ZB-1) was deprotected by heating in formic acid as described for ZA-1. The excess formic acid was evaporated and the residue was chromatographed on silica gel eluting with DCM followed by DCM/MeOH 20:1 to give 7 mg of the title product. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.9 (1H, br s), 9.53 (1H, br s), 8.98 (1H, s), 8.80 (1H, d), 8.71 (1H, d), 7.65(2H, d), 7.54(2H, d), 6.25(1H, s), 2.20(3H, s), 1.35(9H, s); MS(ESI ⁺ )=418.31(M+H) ⁺ .

Example ZB-4: 2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-6-nitro-2H-2,3-di Aziridine-1-one

12mg of 6-nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-2,3 -Naphthyridine-1-one (preparation see ZB-1) was deprotected by heating in formic acid as described for ZB-1. Excess formic acid was evaporated and the residue was chromatographed on silica gel eluting with DCM followed by DCM/MeOH 20:1 to give 5 mg of the title product. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.9 (1H, br s), 9.78 (1H, s), 9.52 (1H, s), 8.65-8.56 (2H, m), 7.65 (2H, d) , 7.53(2H, d), 6.26(1H, s), 2.20(3H, s), 1.35(9H, s); MS(ESI ⁺ )=418.32(M+H) ⁺ .

Example ZB-5: 6-amino-2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-diazepine Xinaphthin-1-one

6-Amino-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl- phenyl )-2H-2,3-diazepine Xanaphthin-1-one : As described for the 7-nitro isomer under ZB-1, for 1.80 g 6-nitro-4-(2-tert-butyl-5-methyl-2H-pyridine Azol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-2,3-naphthyridine-1-one (preparation see ZB-1) was hydrogenated to give 1.11 g of 6-amino-2,3-phthalazinone.

6-Amino-2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3- naphthyridine -1- one : 30mg 6-amino-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-2,3 -Naphthyridine-1-one was dissolved in 0.5 ml MeOH. 2 ml concentrated HCl was added and the mixture was heated to 80°C for 7 hours. The mixture was evaporated under vacuum, the residue was dissolved in DCM and washed with sodium bicarbonate solution. Removal of DCM yielded 12 mg of the title product. ¹ H-NMR: (400MHz, D ₆ -DMSO) 11.75 (1H, br s), 8.75 (1H, brs), 8.00 (1H, d), 7.59 (2H, d), 7.46 (2H, d), 7.27 (1H, s), 7.05(1H, d), 6.16(brs, 2H), 2.17(3H, s), 1.33(9H, s); MS(ESI ⁺ )=389.22(M+H) ⁺ .

Example ZB-6: 6-bromo-2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3-di Aziridine-1-one

6-Bromo-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl- phenyl )-2H-2,3-di Naphthalene-1-one : Under argon, at 100°C, make 11 mg of 4,6-dibromo-2-(4-tert-butyl-phenyl)-2H-2,3-naphthyridine -1-one (see ZA-1 for preparation) with 39.0 mg of 1-tert-butyl-3-methyl-1H-pyrazol-5-ylamine, 132 mg of cesium carbonate, 7.0 mg of tris-(dibenzylideneacetone )-dipalladium and 8.8 mg 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene were stirred until HPLC showed complete conversion. The solvent was removed under vacuum, the residue was taken up in DCM and washed with dilute HCl. The DCM was removed and chromatography on silica gel with first heptane then heptane/EtOAc 8:2 gave 25 mg of the title product.

6-Bromo-2-(4-tert-butyl-phenyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-2,3- naphthyridine - 1- Ketone : At 90 ° C, 15 mg of 6-bromo-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl )-2H-2,3-Naphthyridine-1-one was heated in formic acid for 5 hours, then evaporated and chromatographed on silica gel (DCM, then DCM/MeOH 40:1). Yield 10 mg. ¹ H-NMR: (400MHz, D ₆ -DMSO) 9.33 (1H, br s), 8.86 (1H, br s), 8.26 (1H, d), 8.80 (1H, d) 7.62 (2H, d), 7.51(2H, d), 6.26(1H, s), 2.20(3H, s), 1.35(9H, s); MS(ESI ⁺ )=452.35(M+H) ⁺ .

Method ZC

Example ZC-1: 2-(4-tert-butyl-2-chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine Xinaphthin-1-one

4-bromo-2-(4-tert-butyl-2-chloro-phenyl)-2H-2,3-phthalazin-1-one : 54mg 4-bromo-2-(4-tert Butyl-phenyl)-2H-2,3-naphthyridine-1-one (prepared according to Procedure R) was dissolved in 5 ml MeOH. Chlorine gas was bubbled through the solution for 2 min at room temperature. Chlorine addition was stopped and the mixture was stirred for 3 days. 29 mg of the title product were isolated by filtration of the resulting suspension. An additional 11 mg was obtained from the filtrate after evaporation and preparative HPLC/MS chromatography.

2-(4-tert-butyl-2-chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1- one : As described in method O, by 4-bromo-2-(4-tert-butyl-2-chloro-phenyl)-2H-2,3-phthalazin-1-one with 1-tert Buchwald reaction of butyl-3-methyl-1H-pyrazol-5-ylamine and subsequent cleavage of N-tert-butyl gives 2-(4-tert-butyl-2-chloro-phenyl)-4-(5 -Methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one. ¹ H-NMR: (400MHz, CDCl ₃ /CD ₃ OD) 8.53 (1H, d), 8.13 (1H, d), 7.94 (1H, t), 7.88 (1H, t) 7.58 (1H, s), 7.46 (2H, s), 6.17(1H, s), 2.24(3H, s), 1.39(9H, s); MS(ESI ⁺ )=408.4(M+H) ⁺ .

Example ZD-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethoxy)-2H-2,3 -Naphthyridine-1-one

7-Nitro-2,3-dihydro-2,3-naphthyridine-1,4-dione : At room temperature, hydrazine hydrate (26.6 g, 0.53 mol) was added in one portion to 4-nitro A stirred mixture of phthalic anhydride (100 g, 0.52 mol) in HOAc (1.0 L). The mixture was heated to 120°C for 2 hours and then allowed to cool to room temperature. The solid was filtered, washed with water (250ml) and dried under vacuum at 50°C for 20 hours to give nitronaphthyridine (95g, 88% yield). Tr＝0.85min m/z(ES ⁺ )(M+H ⁺ )208

6-nitro-4-bromo-2H-2,3-naphthyridine-1-one and 7-nitro-4-bromo-2H-2,3-naphthyridine -1-one : 7-nitro-2,3-dihydro-2,3-naphthyridine-1,4-dione (95.0g, 0.46mol) was suspended in DCE (1.0L), and phosphorus pentabromide (789.0 g, 1.83 mol) was added in three portions and the reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured onto ice (2.5 kg), the resulting precipitate was filtered and washed with water to give the crude product (160.0 g).

The crude material was suspended in HOAc (1.60 L) and heated to 125 °C for 2 hours. The reaction was cooled to room temperature and poured onto ice (1.5 kg) and the resulting precipitate was filtered. The solid was washed with water and dried to give the title compound (84 g, 68% yield, 1:1 mixture of isomers) as a yellow solid. 7-nitro: δ _H (400MHz, DMSO), 13.29(1H), 8.83(1H, d), 8.79(1H, dd), 8.61(1H, dd), 8.54(1H, d), 8.46(1H, d), 8.16(d)Tr=1.11min, m/z(ES ⁺ )(M+H) ⁺ 269 & 271

7-nitro-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one: 6-nitro-4-bromo-2H-2,3-diazepine A mixture of xinaphthalen-1-one and 7-nitro-4-bromo-2H-2,3-phthalazin-1-one (84 g, 0.31 mol) was dissolved in DMF (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at room temperature for 30 minutes, then 2-bromo-propane (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours, LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g, 0.15 mol) and the reaction was stirred for an additional 24 hours. DMF was removed under vacuum and the resulting crude material was purified by sequential column chromatography (elution: 92% heptane, 8% EtOAc) to give the title compound (38.8 g, 40% yield) as pale yellow solid. δ _H (400 MHz, DMSO), 8.88 (1H, d), 8.87 (1H, dd), 8.16 (1H, d), 5.19 (1H, m), 1.13 (6H, d).

7-Amino-2-isopropyl-4-bromo-2H-2,3-naphthyridine-1-one : 7-nitro-2-isopropyl-4-bromo-2H-2 , 3-Naphthyridine-1-one (4.6 g, 0.015 mol) was dissolved in a 5:1 mixture of EtOH and water (150 ml). To this solution were added iron powder (2.14 g, 0.039 mol) and concentrated HCl (1 ml), and the mixture was heated to 80° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, which was washed with EtOH (100 ml), and the solution was concentrated under vacuum to give the title compound (4.2 g, 98% yield), It is a white solid. δ _H (400MHz, DMSO), 7.56(1H, d), 7.28(1H, s), 7.13(1H, d), 6.47(2H, s), 5.24-5.09(1H, m), 1.23(6H, d )Tr＝1.34min m/z(ES ⁺ )(M+H) ⁺ 282, 284

7-Hydroxy-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one : Slowly add concentrated sulfuric acid (17ml) to 7-amino-2-isopropyl-4- Solution of bromo-2H-2,3-phthalazin-1-one (4.6 g, 0.016 mol) in HOAc (50 ml). The reaction mixture was cooled to 0°C and a solution of sodium nitrite (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 minutes at 0°C, after which time urea (0.55 g, 0.009 mol) and cold water (50 ml) were added. The reaction mixture was then carefully added to a refluxing mixture of sulfuric acid (28ml) in water (115ml) and the reaction was stirred at reflux for a further 10 minutes before being allowed to cool to room temperature. After standing, an orange precipitate was observed which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder. δ _H (400MHz, DMSO), 11.18(1H, br s), 7.93(1H, d), 7.71(1H, d), 7.53(1H, dd), 5.34-5.26(1H, m), 1.42(6H, d)

4-Bromo-2-isopropyl-7-(2-methylthio-ethoxy)-2H-2,3-naphthyridine-1-one : to 7-hydroxyl-2-isopropyl - To a solution of 4-bromo-2H-2,3-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml) was added potassium carbonate (2 g, 0.014 mol). After 5 minutes, 2-chloroethylmethylsulfide (0.34 g, 0.0028 mol) was added and the solution was heated to 100° C. for 24 hours. After this time LC-MS showed complete consumption of starting material, the mixture was cooled, concentrated in vacuo, purified by flash column chromatography (elution: 70% heptane, 30% EtOAc) to give the title compound (0.3 g, 24% yield ), which is a white solid.

2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethoxy)-2H-2,3- naphthyridine- 1-Keto (ZD-1) : 4-Bromo-2-isopropyl-7-(2-methylthio- Ethoxy)-2H-2,3-naphthyridine-1-one (0.3g, 0.8mmol), sodium tert-butoxide (0.112g, 1.2mmol), 3-amino-5-methylpyrazole ( 0.107g, 1.2mmol), in a mixture of three-(dibenzylideneacetone)-dipalladium (0.038g, 0.042mmol) and 2-(di-tert-butylphosphine)-biphenyl (0.025g, 0.084mmol) . The reaction mixture was heated to 100 °C for 20 hours with stirring, then cooled to room temperature. Diethyl ether (10ml) was added and the precipitated solid was filtered to give the crude product as a gray solid. Flash column chromatography (elution: 95% EtOAc, 5% MeOH) provided the title compound as a white solid (0.070 g, 7% yield).

Example ZD-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethoxy)-2H-2,3 -Naphthyridine-1-one

_δH (400MHz, DMSO)11.95-11.83(1H,m), 9.10(1H,s), 8.39(1H,d), 7.68(1H,d), 7.46(1H,dd), 6.33(1H,s) , 5.29-5.20 (1H, m), 4.33 (2H, t), 2.91 (2H, t), 2.24 (3H, s), 2.18 (3H, s), 1.32 (6H, d) Tr = 1.77min, m /z(ES ⁺ )(M+H) ⁺ 374.26.

Example ZD-2: 2-isopropyl-7-(2-methoxy-ethoxy)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3 -Naphthyridine-1-one

δ _H (400MHz, DMSO) 9.18(1H, s), 8.36(1H, d), 7.68(1H, d), 7.47(1H, dd), 6.34(1H, s), 5.30-5.18(1H, m) , 4.28(2H, t), 3.72(2H, t), 3.33(3H, s), 2.25(3H, s), 1.32(6H, d) Tr=1.12min, m/z(ES ⁺ )(M+ H) ⁺ 358.39.

Example ZD-3: 3-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yloxy]-propane-1-sulfonic acid dimethylamide

δ _H (400MHz, DMSO) 11.89(1H, br s), 9.10(1H, s), 8.39(1H, d), 7.68(1H, d), 7.47(1H, dd), 6.33(1H, s), 5.29-5.19(1H, m), 4.27(2H, t), 3.27-3.21(2H, m), 2.80(6H, s), 2.24(3H, s), 2.21-2.14(2H, m), 1.31( 6H, d) Tr=1.23min, m/z(ES ⁺ )(M+H) ^+449.19 .

Example ZD-4: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-[3-(morpholine-4-sulfonyl)-propoxy] -2H-2,3-naphthyridine-1-one.

δ _H (400MHz, DMSO) 11.88(1H, br s), 9.10(1H, s), 8.39(1H, d), 7.68(1H, d), 7.47(1H, dd), 6.33(1H, s), 5.30-5.18(1H, m), 4.27(2H, t), 3.66-3.62(4H, m), 3.31-3.25(2H, m), 2.24(3H, s), 2.22-2.15(2H, m), 1.32(6H,d)Tr=1.60min, m/z(ES ⁺ )(M+H) ^+491.22 .

Example ZD-5: 7-(2-Dimethylamino-ethoxy)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one

δ _H (400MHz, DMSO)8.41(1H,d), 7.67(1H,d), 7.45(1H,dd), 6.32(1H,s), 5.32-5.16(1H,m), 4.23(2H,t) , 2.68(2H, t), 2.23(9H, s), 1.32(6H, d) Tr=1.38min, m/z(ES ⁺ )(M+H) ⁺ 371.28.

Example ZD-6: 2-isopropyl-7-(2-methanesulfinyl-ethoxy)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one

To 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethoxy)-2H-2,3-naphthyridine To a solution of 1-one (0.077 g, 0.23 mmol) in DCM (2 ml) was added m-chloroperbenzoic acid (0.040 g, 0.23 mmol) in portions. The solution was stirred at room temperature for 1 hour. After this time LC-MS showed complete consumption of starting material and solvent was removed under vacuum. Preparative thin layer chromatography (elution: 50% EtOAc, 50% EtOH) provided the title compound (0.015 g, 14% yield) as a pale yellow solid.

δ _H (400MHz, DMSO) 11.93(1H, br s), 9.16(1H, br s), 8.42(1H, d), 7.72(1H, d), 7.50(1H, dd), 6.33(1H, s) , 5.29-5.20(1H, m), 4.62-4.55(1H, m), 4.52-4.43(1H, m), 3.17-3.09(2H, m), 2.67(3H, s), 2.23(3H, s) , 1.32(6H, d)Tr=1.02min, m/z(ES ⁺ )(M+H) ⁺ 390.26.

Example ZD-7: 2-isopropyl-7-(2-methylsulfonyl-ethoxy)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3 -Naphthyridine-1-one

To 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethoxy)-2H-2,3-naphthyridine To a solution of 1-one (0.077 g, 0.23 mmol) in DCM (2 ml) was added m-chloroperbenzoic acid (0.080 g, 0.46 mmol) in portions. The solution was stirred overnight at room temperature. After this time LC-MS showed complete consumption of starting material and solvent was removed under vacuum. Preparative thin layer chromatography (elution: 50% EtOAc, 50% EtOH) provided the title compound (0.010 g, 9% yield) as a white solid.

_δH (400MHz, DMSO)11.90(1H,s), 9.12(1H,s), 8.42(1H,d), 7.72(1H,d), 7.53(1H,dd), 6.35(1H,s), 5.31 -5.16(1H, m), 4.54(2H, t), 3.70(2H, t), 3.11(3H, s), 2.24(3H, s), 1.32(6H, d)Tr=1.59min, m/z (ES ⁺ )(M+H) ⁺ 406.22.

Method ZE:

Example ZE-1: 2-isopropyl-7-[methyl-(2-methylthio-ethyl)-amino]-4-(5-methyl-1H-pyrazol-3-ylamino) -2H-2,3-naphthyridine-1-one

(1-Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-tert-butyl carbamate :

7-Amino-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one (1.88 g, 6.7 mmol) was dissolved in DMF (20 ml). To this was added NaH (60%, 0.8 g, 20.1 mmol) as a suspension in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes then _Boc2O (4.36 g, 20.1 mmol) as a solution in DMF (5 ml) was added in one portion and the reaction mixture was heated to 70 °C for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was added carefully, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was dissolved in a 1:1 mixture of THF/EtOH (10 ml) and aqueous NaOH (50 wt % solution, 10 ml) was added in one portion and the reaction mixture was vigorously stirred for 30 min. After this time, the mixture was partitioned between water (20ml) and EtOAc (50ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to give the title compound (2.2 g, 88% yield) as a light brown solid. δ _H (400MHz, DMSO), 8.32(1H, d), 8.19(1H, s), 7.88(1H, d), 7.41(1H, s), 5.46-5.31(1H, m), 1.52(9H, s ), 1.41(6H, d)Tr=1.73min, m/z(ES ⁺ )(M+H) ^+382.22 .

4-bromo-2-isopropyl-7-methylamino-2H-2,3-naphthyridine-1-one : (1-bromo-3-isopropyl-4-oxo- tert-Butyl 3,4-dihydro-2,3-naphthyridine-6-yl)-carbamate (2.2 g, 5.7 mmol) was dissolved in THF (10 ml). To this was added NaH (60%, 0.34 g, 8.6 mmol) as a suspension in THF (5 ml). The mixture was stirred at room temperature for 30 minutes, then methyl iodide (1.4ml, 23.0mmol) was added in one portion as a solution in THF (5ml) and the reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was added carefully, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo.

The residue was dissolved in 20% TFA/DCM solution (10 ml) and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was concentrated under vacuum to afford a brown oil. Heptane (20ml) was added and the mixture concentrated in vacuo. Diethyl ether (10 ml) was added to the residue and the resulting precipitate was filtered and dried under vacuum to give the title compound (1.14 g, 68% yield) as a light brown solid. Tr=1.50min, m/z(ES ⁺ )(M+H) ^+296.16 .

4-Bromo-2-isopropyl-7-[methyl-(2-methylthio-ethyl)-amino]-2H-2,3-naphthyridine-1-one : 4-bromo Geno-2-isopropyl-7-methylamino-2H-2,3-naphthyridine-1-one (0.095 g, 0.32 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.015 g, 0.38 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 30 minutes, then chloroethylmethylsulfide (0.042 g, 0.38 mmol) was added in one portion as a solution in DMF (1 ml), and the reaction mixture was heated to 70 °C for 24 hours. After this time, the reaction mixture was cooled to room temperature and water (10ml) was added carefully, the mixture was extracted with EtOAc (3 x 10ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo. Flash column chromatography (elution: 70% hexanes, 30% EtOAc) gave the title compound (0.021 g, 18% yield) as a white solid. δ _H (400MHz, CDCl ₃ ), 7.73(1H, d), 7.48(1H, d), 7.13(1H, d), 5.41-5.29(1H, m), 3.71(2H, t), 3.18(3H, s), 3.15 (3H, s), 2.73 (2H, t), 1.41 (6H, d).

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 2-isopropyl-7-[methyl-(2-methylthio-ethyl)-amino]-4-(5 -Methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (B-1).

Example ZE-1: 2-isopropyl-7-[methyl-(2-methylthio-ethyl)-amino]-4-(5-methyl-1H-pyrazol-3-ylamino) -2H-2,3-naphthyridine-1-one

δ _H (400MHz, DMSO), 9.11(1H, s), 8.19(1H, d), 7.35(1H, d), 7.28(1H, dd), 6.34(1H, s), 5.29-5.19(1H, m ), 3.71(2H, t), 3.09(3H, s), 2.69(2H, t), 2.25(3H, s), 2.14(3H, s), 1.31(6H, d)Tr=1.80min, m/ z(ES ⁺ )(M+H) ⁺ 387.26.

Example ZE-2: 2-isopropyl-7-[(2-methoxy-ethyl)-methyl-amino]-4-(5-methyl-1H-pyrazol-3-ylamino) -2H-2,3-naphthyridine-1-one

δ _H (400MHz, DMSO), 11.83(1H, s), 8.87(1H, s), 8.21(1H, d), 7.34(1H, d), 7.25(1H, d), 6.34(1H, s), 5.30-5.18(1H,m), 3.66(2H,t), 3.53(2H,t), 3.25(3H,s), 3.06(3H,s), 2.23(3H,s), 1.30(6H,d) Tr=1.69min, m/z(ES ⁺ )(M+H) ^+371.32 .

Example ZE-3: 7-[(2-Dimethylamino-ethyl)-methyl-amino]-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino )-2H-2,3-naphthyridine-1-one

δ _H (400MHz, DMSO), 11.83(1H, br s), 8.90(1H, br s), 8.21(1H, d), 7.33(1H, d), 7.22(1H, d), 6.33(1H, br s), 5.29-5.17(1H, m), 3.61-3.52(2H, m), 3.05(3H, t), 2.41(2H, t), 2.23(3H, s), 2.20(6H, s), 1.30 (6H, d) Tr=1.01min, m/z(ES ⁺ )(M+H) ⁺ 384.22.

Method ZF:

Example ZF-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethylthio)-2H-2,3 -Naphthyridine-1-one

7-Mercapto-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one : Concentrated sulfuric acid (5ml) was added dropwise to 7-amino-2-isopropyl-4 -A solution of bromo-2H-2,3-phthalazin-1-one (1.5 g, 5.3 mmol) in HOAc (15 ml) and the solution was cooled to 0°C. A solution of sodium nitrite (0.5 g, 7.4 mmol) in water (2.5 ml) was added dropwise and the reaction mixture was stirred at 0°C for 20 minutes, followed by the addition of urea (0.17 g, 2.8 mmol) in one portion. Next, the reaction mixture was added dropwise to a solution of potassium ethyl xanthate (6 g, 37.7 mmol) in water (7.5 ml) and the mixture was heated to 80° C. for 30 minutes. After this time, the reaction mixture was cooled to room temperature and DCM (100ml) was added. The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was taken up in THF (10ml), NaOH (4.95g, 0.12mmol) was added in one portion and the mixture was heated to reflux for 24 hours. Next, the mixture was cooled to room temperature and the suspension was acidified to pH 2 with concentrated HCl. DCM (100ml) was added, the organic layer was separated and then washed with HCl (1M, 20ml) and water (20ml). The organic layer was extracted with NaOH (1M, 200ml), the aqueous layer was separated and acidified to pH 1 with concentrated HCl. The mixture was extracted with DCM (2 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.77g, 48% yield) as a light brown solid. It was used without further purification.

4-Bromo-2-isopropyl-7-(2-methylthio-ethylthio)-2H-2,3-naphthyridine-1-one :

To a solution of crude 7-mercapto-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one (0.40 g, 1.3 mmol) in DMF (8 ml), NaH (60%, 0.064 g, 1.6 mmol) was added in portions. After stirring for 5 minutes, chloroethylmethylsulfide (0.17 g, 1.6 mmol) was added dropwise. The mixture was heated to 60 °C for 2 hours, then the mixture was concentrated in vacuo and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. δ _H (400MHz, DMSO), 8.03(1H, d), 7.92(1H, d), 7.81(1H, d), 5.26-5.15(1H, m), 3.41(2H, t), 2.78(2H, t ), 2.15 (3H, s), 1.36 (6H, d).

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2- Methylthio-ethylthio)-2H-2,3-naphthyridine-1-one (ZF-1).

Example ZF-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylthio-ethylthio)-2H-2,3 -Naphthyridine-1-one

Tr=1.33min, m/z(ES ⁺ )(M+H) ^+390.23 .

Example ZF-2: 2-isopropyl-7-(2-methylsulfonyl-ethanesulfonyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3 -Naphthyridine-1-one

Potassium monopersulfate (oxone) (0.12 g, 0.07 mmol) was added in one portion to 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2- Methylthio-ethylthio)-2H-2,3-phthalazin-1-one (0.013g, 0.03mmol) in a stirred solution of a 4:1 mixture of dioxane/water (1.2ml), And the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5ml) and the solution was extracted with EtOAc (3 x 75ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.008g, 57% yield) as a white solid. δ _H (400MHz, DMSO) 9.69(1H, br s), 8.75(1H, d), 8.71(1H, d), 8.47(1H, dd), 6.40(1H, s), 5.31-5.22(1H, m ), 3.95-3.89 (2H, m), 3.48-3.42 (2H, m), 3.06 (3H, s), 2.29 (3H, s), 1.36 (6H, d) Tr=1.61min, m/z (ES ⁺ )(M+H) ⁺ 454.10.

Method ZG:

Example ZG-1: 7-(2-Dimethylamino-ethoxy)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one

(1-Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-tert-butyl carbamate :

7-Amino-2-isopropyl-4-bromo-2H-2,3-phthalazin-1-one (1.88 g, 6.7 mmol) was dissolved in DMF (20 ml). To this was added NaH (60%, 0.8 g, 20.1 mmol) as a suspension in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes followed by the addition of _Boc2O (4.36 g, 20.1 mmol) in DMF (5 ml) in one portion and the reaction mixture was heated to 70 °C for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was added carefully, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was dissolved in a 1:1 mixture of THF/EtOH (10 ml), and aqueous NaOH (50 wt % solution, 10 ml) was added in one portion and the reaction mixture was stirred vigorously for 30 min. After this time, the mixture was partitioned between water (20ml) and EtOH (50ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to give the title compound (2.2 g, 88% yield) as a light brown solid. δ _H (400MHz, DMSO), 8.32(1H, d), 8.19(1H, s), 7.88(1H, d), 7.41(1H, s), 5.46-5.31(1H, m), 1.52(9H, s ), 1.41(6H, d)Tr=1.73min, m/z(ES ⁺ )(M+H) ^+382.22 .

7-(2-Dimethylamino-ethoxy)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3- naphthyridine -1-ketone : (1-bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthalene-6-yl)-carbamic acid tert-butyl ester ( 0.75g, 1.96mmol) was dissolved in DMF (10ml). To this was added NaH (60%, 0.2 g, 4.9 mmol) as a suspension in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, then 1-bromo-2-methoxyethane (0.4 g, 2.9 mmol) was added in one portion as a solution in DMF (5 ml), and the reaction The mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was cooled to room temperature and water (20ml) was carefully added, the mixture was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried ( _MgSO4 ), filtered, concentrated in vacuo and the residue The material was subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to provide (1-bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-di Azinaphthalen-6-yl)-(2-dimethylamino-ethyl)-carbamic acid tert-butyl ester (0.2 g, 23% yield) as a white solid.

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 2-isopropyl-7-[methyl-(2-methylthio-ethyl)-amino]-4-(5 -Methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one.

The residue was dissolved in 20% TFA/DCM solution (5 ml), and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was concentrated under vacuum to afford a brown oil. Heptane (2ml) was added and the mixture was concentrated in vacuo. Diethyl ether (1 ml) was added to the residue and the resulting precipitate was filtered, dried under vacuum to afford the title compound (0.061 g, 6% yield) as a pale yellow solid.

Example ZG-1: 7-(2-Dimethylamino-ethoxy)-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2, 3-Naphthyridine-1-one

δ _H (400MHz, DMSO), 9.41(1H, br s), 8.95(1H, s), 8.18(1H, d), 7.35(1H, d), 7.14(1H, dd), 6.33(1H, s) , 5.29-5.17(1H, m), 3.60-3.53(2H, m), 3.33-3.26(2H, m), 2.88-2.84(6H, m), 2.24(3H, s), 1.31(6H, d) Tr=1.50min, m/z(ES ⁺ )(M+H) ^+370.38 .

Method ZH:

Example ZH-1: 7-cyclopropylmethoxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine Xinaphthin-1-one

1,4-Dioxo-1,2,3,4-tetrahydro-2,3-naphthyridine-6-carboxylic acid : At room temperature, hydrazine hydrate (26 g, 0.52 mol) was A stirred mixture of 1,2,4-benzenetricarboxylic anhydride (100 g, 0.52 mol) in HOAc (1.0 L) was added. The mixture was heated to 120°C for 2 hours and then allowed to cool to room temperature. The solid was filtered, washed with water (250ml) and dried under vacuum at 50°C for 20 hours to give the title compound (91g, 85% yield).

1-bromo-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid : 1,4-dioxo-1,2,3,4-tetrahydro -2,3-Naphthalene-6-carboxylic acid (91.0 g, 0.44 mol) was suspended in DCE (1.0 L), phosphorus pentabromide (761.0 g, 1.77 mol) was added in three portions and the reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured onto ice (2.5 kg) and the resulting precipitate was filtered, washed with water to give the crude product (130.0 g). The crude material was suspended in HOAc (1.6 L) and heated to 125 °C for 2 hours. The reaction was cooled to room temperature and poured onto ice (1.5 kg) and the resulting precipitate was filtered. The solid was washed with water and dried to give the title compound (85 g, 73% yield) as a pale yellow solid. Tr＝0.94min, m/z(ES ⁺ )(M+H) ⁺ 310 & 312

1-Bromo-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid ethyl ester : add concentrated sulfuric acid (40ml) to 1-bromo-4-oxo- 3,4-Dihydro-2,3-naphthyridine-6-carboxylic acid (85 g, 0.32 mol) was stirred in EtOH (500 ml) and the mixture was heated to reflux for 48 hours. After this time, the reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was partitioned between EtOAc (1 L) and saturated NaHCO ₃ (500 ml), the organic layer was separated and washed with water (500 ml) before being dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound (30 g, 31% yield) as a white solid. Tr＝1.23min, m/z(ES ⁺ )(M+H) ⁺ 297 & 299

1-bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthyridine-6-carboxylic acid ethyl ester: 1-bromo-4-oxo- Ethyl 3,4-dihydro-2,3-naphthyridine-6-carboxylate (6 g, 0.02 mol) was dissolved in DMF (60 ml). To this was added NaH (60%, 0.97 g, 0.024 mol) as a DMF suspension (5 ml). The mixture was stirred at room temperature for 30 minutes, then 2-bromo-propanol (3.7 g, 0.03 mol) was added in one portion as a solution in DMF (5 ml). The reaction mixture was stirred for 48 hours, after which LC-MS showed complete consumption of starting material. DMF was removed under vacuum and the resulting residue was partitioned between DCM (100ml) and water (100ml), the organic layer was dried ( _MgSO4 ), filtered and concentrated under vacuum. The resulting yellow oil was recrystallized from MeOH to give the title compound (2.3 g, 34% yield) as a white solid. Tr＝1.75min, m/z(ES ⁺ )(M+H) ⁺ 339 & 341

4-bromo-7-hydroxymethyl-2-isopropyl-2H-2,3-naphthyridine-1-one : 1-bromo-3-isopropyl-4-oxo-3 , ethyl 4-dihydro-2,3-naphthyridine-6-carboxylate (2.3 g, 6.8 mmol) was suspended in THF (50 ml) and cooled to 0°C. To the suspension was added _LiBH4 (5.1 ml of a 2M solution in THF, 10.2 mmol) dropwise, and the suspension was allowed to warm to room temperature and stirred for 24 hours. After this time, LC-MS showed 50% starting material remaining. To this was added _LiBH4 (1.7ml of a 2M solution in THF, 3.4mmol) and the reaction mixture was stirred for a further 3 hours. The reaction was cooled to 0°C, saturated _NH4Cl (40ml) was added and the reaction mixture was then partitioned between water (50ml) and DCM (150ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting residue was then purified by flash column chromatography (elution: 50% toluene, 30% EtOAc, 20% DCM) to afford the title compound (0.9 g, 43% yield) as a white solid. δ _H (400MHz, DMSO), 8.28(1H, s), 7.96(1H, d), 7.88(1H, d), 5.64(1H, t), 5.31-5.18(1H, m), 4.78(2H, d ), 1.35(6H, d)Tr=1.31min, m/z(ES ⁺ )(M+H) ⁺ 297 & 299

4-bromo-7-bromomethyl-2-isopropyl-2H-2,3-naphthyridine-1-one : 4-bromo-7-hydroxymethyl-2-isopropyl - A solution of 2H-2,3-phthalazin-1-one (0.74g, 2.5mmol) in MeCN (5ml) was added dropwise to TMSBr (0.9g, 6.3mmol) and LiBr (0.41g, 5mmol) in MeCN (15ml) in a stirred suspension. The reaction mixture was heated to 80 °C for 24 hours, then the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The resulting residue was purified by flash column chromatography (elution: 85% heptane, 15% EtOAc) to afford the title compound (0.4 g, 44% yield) as a white solid. δ _H (250MHz, DMSO), 8.37(1H, s), 8.03(1H, d), 7.94(1H, d), 5.26-5.09(1H, m), 4.93(2H, s), 1.35(6H, d ).

4-Bromo-7-cyclopropylmethoxymethyl-2-isopropyl-2H-2,3-naphthyridine-1-one : Dissolve cyclopropylmethanol (0.05ml, 0.67mmol) in THF (1 ml). To this was added a portion of NaH (60%, 0.028 g, 0.72 mmol). The mixture was stirred at room temperature for 5 minutes followed by the addition of 4-bromo-7-bromomethyl-2-isopropyl-2H-2,3-naphthyridine in THF (1 ml) in one portion 1-Kone (0.2 g, 0.56 mmol) and the reaction mixture was stirred for 1 hour. Subsequent LC-MS showed complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.17 g, 87% yield rate), which is a pale yellow oil. Tr=1.80min, m/z(ES ⁺ )(M+H) ⁺ 351 & 353

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 7-cyclopropylmethoxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazole- 3-ylamino)-2H-2,3-phthalazin-1-one (E-1).

Example ZH-1: 7-cyclopropylmethoxymethyl-2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-diazepine Xinaphthin-1-one

δ _H (400MHz, DMSO), 11.92(1H, br s), 9.15(1H, s), 8.42(1H, d), 8.24(1H, s), 7.80(1H, d), 6.36(1H, s) , 5.29-5.21(1H, m), 4.68(2H, s), 2.25(2H, s), 1.32(6H, d), 1.12-1.03(1H, m), 0.53-0.47(2H, m)Tr= 1.80min, m/z(ES ⁺ )(M+H) ⁺ 368.35.

Example ZH-2: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(pyridin-3-ylmethoxymethyl)-2H-2, 3-Naphthyridine-1-one

_δH (400MHz, DMSO), 11.92(1H, s), 9.17(1H, s), 8.55-8.53(1H, m), 8.45(1H, d), 8.31-8.29(1H, m), 7.89-7.81 (2H, m), 7.52 (1H, d), 7.34-7.30 (1H, m), 6.37 (1H, s), 5.29-5.21 (1H, m), 4.83 (2H, s), 4.68 (2H, s ), 2.25(3H, s), 1.32(6H, d) Tr=1.55min, m/z(ES ⁺ )(M+H) ^+405.31 .

Method ZI:

Example Z1-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthiomethyl-2H-2,3-naphthyridine- 1-keto

4-Bromo-2-isopropyl-7-methylthiomethyl-2H-2,3-naphthyridine-1-one : Sodium methanethiolate (0.23 g, 3.33 mmol) was dissolved in THF ( 1ml) and added dropwise 4-bromo-7-bromomethyl-2-isopropyl-2H-2,3-phthalazin-1-one (0.4g, 1.11mmol) in THF (10ml) in the solution. The mixture was stirred at room temperature for 3 hours, after which LC-MS showed complete consumption of starting material. The reaction mixture was diluted with water (20ml) and extracted with EtOAc (50ml). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was subjected to flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.29 g, 79% yield) as a white solid.

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthio Methyl-2H-2,3-phthalazin-1-one (F-1).

Example ZI-1: 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthiomethyl-2H-2,3-naphthyridine- 1-keto

δ _H (400MHz, DMSO), 9.15(1H, s), 8.41(1H, d), 8.20(1H, d), 7.82(1H, d), 6.36(1H, s), 5.31-5.19(1H, m ), 3.90(2H, s), 2.24(3H, s), 1.95-1.93(3H, m), 1.32(6H, d) Tr=1.75min, m/z(ES ⁺ )(M+H) ⁺ 344.29 .

Example ZI-2: 2-isopropyl-7-methanesulfonylmethyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine- 1-keto

Potassium monopersulfate (0.43 g, 0.7 mmol) was added in one portion to 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylthiomethyl- A stirred solution of 2H-2,3-phthalazin-1-one (0.06 g, 0.17 mmol) in a 4:1 mixture of dioxane/water (1.2 ml) and the reaction mixture was stirred at room temperature for 1 hour . The reaction mixture was diluted with water (5ml) and the solution was extracted with EtOAc (3 x 75ml), the organic layers were combined, dried ( _MgSO4 ), filtered and concentrated in vacuo to give the title compound (0.013g, 20% yield) as a white solid. δ _H (400MHz, DMSO) 9.23(1H, s), 8.48(1H, d), 8.38(1H, d), 7.89(1H, dd), 6.36(1H, s), 5.33-5.20(1H, m) , 4.77 (2H, s), 2.96 (3H, s), 2.25 (3H, s), 1.33 (6H, d) Tr = 1.58 min, m/z (ES ⁺ ) (M + H) ⁺ 376.24.

Method ZJ:

Example ZJ-1: N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yl]-2-methoxy-N-methyl-acetamide

N-(1-Bromo-3-isopropyl-4-oxo-3,4-dihydro-2,3-naphthyridine-6-yl)-2-methoxy-N- methyl - Acetamide : 4-Bromo-2-isopropyl-7-methylamino-2H-2,3-naphthyridine-1-one (0.5 g, 1.69 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.19 g, 5.1 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 30 minutes, then methoxyacetyl chloride (0.27 g, 2.5 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 hours. After this time, water (10ml) was added carefully, the mixture was extracted with EtOAc (3 x 10ml), the combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. Flash column chromatography (elution: 50% hexanes, 50% EtOAc) afforded the title compound (0.47 g, 76% yield) as a white solid.

This material was then used in the Buchwald reaction as described in Method ZC to give the corresponding 2-isopropyl-7-methylamino-4-(5-methyl-1H-pyrazol-3-ylamino) -2H-2,3-naphthyridine-1-one.

2-isopropyl-7-methylamino-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-2,3-naphthyridine-1-one (0.4g, 1.3mmol) was dissolved in DMF (5ml). To this was added NaH (60%, 0.1 g, 2.6 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 5 minutes then methoxyacetyl chloride (0.28 g, 2.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. After this time, water (10ml) was added carefully, the mixture was extracted with EtOAc (3 x 10ml), the combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was dissolved in THF (5ml) and heated at 60°C in the presence of solid sodium hydroxide (100mg) for 2 hours. After this time, the mixture was concentrated under vacuum and subjected to flash column chromatography (elution: 95% EtOAc, 5% MeOH) to give N-[3-isopropyl-1-(5-methyl-1H-pyrazole-3 -ylamino)-4-oxo-3,4-dihydro-2,3-naphthyridine-6-yl]-2-methoxy-N-methyl-acetamide (0.06g, 12% yield) as a white solid.

Example ZJ-1: N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yl]-2-methoxy-N-methyl-acetamide

δ _H (400MHz, DMSO), 9.25(1H, s), 8.48(1H, d), 8.17(1H, d), 7.89(1H, dd), 6.35(1H, s), 5.32-5.17(1H, m ), 4.05-3.92(2H, m), 3.28(3H, s), 3.22(3H, s), 2.25(3H, s), 1.32(6H, d) Tr=1.56min, m/z(ES ⁺ ) (M+H) ⁺ 385.29.

Example ZJ-2: N-[3-(3,5-difluoro-benzyl)-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4 -Dihydro-2,3-naphthyridine-6-yl]-2-methoxy-N-methyl-acetamide

δ _H (400MHz, DMSO), 9.32(1H, br s), 8.49(1H, d), 8.20(1H, d), 7.92(1H, dd), 7.22-7.02(3H, m), 6.06(1H, br s), 5.26(2H, s), 4.01(2H, br s), 3.29(3H, s), 3.22(3H, s), 2.17(1H, s) Tr=1.80min, m/z(ES ⁺ )(M+H) ⁺ 468.95.

Example ZJ-3: N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-yl]-N-methyl-2-phenoxy-acetamide

δ _H (400MHz, DMSO), 9.41(1H, s), 8.50(1H, d), 8.26(1H, s), 7.99(1H, d), 7.31-7.13(4H, m), 7.10-7.05(1H , m), 6.91 (1H, t), 6.87-6.78 (2H, m), 6.08 (1H, s), 5.28 (2H, s), 4.78 (2H, br s), 2.19 (3H, s) Tr = 2.07min，m/z(ES ⁺ )(M+H) ⁺ 530.97.

Method ZK:

Example ZK-1: 4-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-ylamino]-butyric acid

4-Bromo-2-isopropyl-7-(2-oxo-pyrrolidin-1-yl)-2H-2,3-naphthyridine-1-one : to 7-amino-2-iso Propyl-4-bromo-2H-2,3-phthalazin-1-one (0.5 g, 1.8 mmol) in DMF (8 ml) was added TEA (0.28 ml, 1.98 mmol). After 5 minutes, 4-chlorobutyryl chloride (0.22ml, 2.0mmol) was added and the solution was stirred at room temperature for 2 hours. After this time LC-MS showed complete consumption of starting material and the mixture was diluted with DCM (30ml) and washed with HCl (1M, 20ml). The organic layer was separated, dried ( _MgSO4 ) and concentrated in vacuo. The residue was subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to give N-(1-bromo-3-isopropyl-4-oxo-3,4-dihydro-2 , 3-naphthyridine-6-yl)-4-chloro-butanamide (0.46 g, 67% yield) as a white solid.

This material was dissolved in DMF (5ml). To this was added NaH (60%, 0.05 g, 1.3 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 2 hours. After this time, water (10ml) was added carefully, the mixture was extracted with EtOAc (3 x 10ml) and the combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to give the title compound (0.15 g, 36% yield) as a pale yellow solid.

This material was then used in the Buchwald reaction as described in Method ZD to give the corresponding 4-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4- Oxo-3,4-dihydro-2,3-naphthyridine-6-ylamino]-butanoic acid (H-1).

Example ZK-1: 4-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-2,3- Naphthalene-6-ylamino]-butyric acid

δ _H (400MHz, DMSO)8.10(1H, s), 7.08(1H, d), 7.02-6.83(2H, m), 6.16(1H, s), 5.27-5.01(1H, m), 3.02(2H, d), 2.08(3H, s), 1.99(2H, t), 1.78-1.54(2H, m), 1.19(6H, d) Tr=1.60min, m/z(ES ⁺ )(M+H) ⁺ 385.43.

Features disclosed in the foregoing description, or in the following claims in their concrete form, or in terms of the manner in which the disclosed function is performed, or in the method or process for achieving the disclosed result, may be taken individually or in combination, as appropriate. Any combination of features is used to realize different forms of the invention.

The foregoing invention has been described in detail by way of illustration and example, for purposes of illustration and understanding. It will be apparent to a person skilled in the art that changes and improvements may be made within the scope of the appended claims. Accordingly, it should be understood that the foregoing description is illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the foregoing description, but should be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

The entire contents of all patents, patent applications and publications cited in this application are hereby incorporated by reference for all purposes to the same extent as if each patent, patent application or publication were individually indicated.

Claims (8)

1. A method of treating a disease mediated by a tyrosine kinase, wherein said tyrosine kinase is BTK or SYK, said method comprising administering a therapeutically effective amount of a compound according to formula I to a patient in need thereof,

in R ¹ , R ² and R ⁴ independently represent R ⁸ -X-, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, hydrogen, halogen, nitro, cyano, -OH, -NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O) NH-OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _1-6 alkyl, -NHC(O)NH-OC _1-6 alkyl, -NHC(O) N(C _1-6 alkyl)-OC _1-6 alkyl, -S(O) ₂ NH-OC _1-6 alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _{1 -6} alkyl, or C _1-6 alkyl optionally substituted once or three times by halogen, hydroxy or alkoxy; R ³ is R ⁸ -X-, R ⁹ -X ¹ -, R ⁸ -X ¹ (CH ₂ ) _m -, R ⁹ -X ¹ (CH ₂ ) _m -, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, hydrogen, halogen, nitro, cyano, -OH, -NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O)NH-OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _{1- 6} Alkyl, -NHC(O)NH-OC _1-6 Alkyl, -NHC(O)N(C _1-6 Alkyl)-OC _1-6 Alkyl, -S(O) ₂ NH-OC _{1 -6} alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _1-6 alkyl, or C _1-6 alkyl optionally substituted one or three times by halogen, hydroxyl or alkoxy base; R ⁸ is C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, aryl-T ³ -, heteroaryl-T ⁴ -, or optionally substituted one to five times by halogen C _1-6 alkyl; R ⁹ is C _1-6 alkyl, wherein said alkyl is substituted one to three times by: hydroxyl, alkoxy, amino, C _1-6 alkylamino, C _1-6 dialkylamino, C _{1-6 6} Alkylthio, C _1-6 Alkylsulfinyl, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfamoyl, C _1-6 Dialkylsulfamoyl, C _1-6 Alkane Sulfonylamino or heterocyclylsulfonyl; X is -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -N(C _1-6 alkyl)C(O)-, -NHC(O)-, - NHC(O)NH-, -NHC(O)N(C _1-6 alkyl)-, -OC(O)N(C _1-6 alkyl)-, -NHS(O) ₂ -, -S( O) ₂ NH-, -S(O) ₂ N(C _1-6 alkyl)-, -S(O) ₂ -, -S(O)-, -C(O)O-, -OC(O )-, -C(O)-, -NH-, -N(C _1-6 alkyl)-, -O- or -S-; X ¹ is -S(O) ₂ -, -S(O)-, -OC(O)-, -C(O)-, -NH-, -N(C _1-6 alkyl)-, -O -or-S-; T ¹ , T ² , T ³ and T ⁴ independently represent a single bond or an alkylene group optionally substituted once or twice by hydroxyl; ^R is hydrogen, _C1-6 alkyl optionally substituted one or several times by halogen or alkoxy, heteroaryl, or phenyl optionally substituted once or twice by : Halogen, -NO ₂ , -OH, -C(O)OH, -C(O)NH-aryl, -C(O)NH ₂ , -C(O)NH-C _1-6 alkyl, - C(O)N(C _1-6 alkyl) ₂ , -C(O)-heterocyclyl, -NH ₂ , -NHC(O)-aryl, -NHC(O)-C _3-7 cycloalkane Base, -NHC(O)-C _1-6 alkyl, -N(C _1-6 alkyl)C(O)-C _1-6 alkyl, -NHC(O)OC _1-6 alkyl,- N(C _1-6 alkyl)C(O)OC _1-6 alkyl, -NHC(O)-C _1-6 alkoxyalkyl, -NH-S(O) ₂ -aryl, -NH -S(O) ₂ -C _1-6 alkyl, -C(O)NH-S(O) ₂ -aryl, -C(O)NH-S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -alkyl, -NH-aryl, -O-aryl, -S(O)-aryl, aryl, heterocyclyl, C _3-7 cycloalkyl, C _1-6 Alkyl, C _1-6 alkoxy or C _1-6 alkylthio, said alkyl, alkoxy and alkylthio are optionally substituted once or three times by: halogen; optionally independently by one Naphthyl substituted by three halogens, phenyl substituted independently by three halogens; 1,3-dihydro-isobenzofuryl, benzo[1,3]dioxol-5- Base, C _3-7 cycloalkyl or C _1-6 alkenyl; Y is an alkylene, alkylene-C(O)- or alkylene-CH(OH)-; m is 1-5; n is 0 or 1; R is ^hydrogen , C _1-6 alkyl, cyano or halogen; and R ⁷ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; or a medicinal salt thereof. 2. The method according to claim 1, wherein R ¹ , R ² , R ⁴ and R ⁶ are hydrogen; R ³ is heterocyclyl-T ² , R ⁸ -X-, R ⁹ -X ¹ -, H(O)CNH- or C _1-6 alkyl optionally substituted by hydroxyl; R ⁸ is a heterocyclic group-T ² ; the heterocyclic group is piperidine, piperazine, N-methylpiperazine or morpholine; T ² is a single bond; X is -O-, -N(C _1-6 alkyl)-, -C(O)NH- or -C(O)N(C _1-6 alkyl)-; n is ⁰ and R is C _1-6 alkyl, or n is 1, Y is C _1-6 alkylene and ^R is optionally substituted phenyl; and R ⁷ is C _1-3 alkyl. 2. The method according to claim 1, wherein said tyrosine kinase is BTK. 3. The method according to claim 1, wherein said tyrosine kinase is SYK. 4. The method according to claim 3, wherein the disease is an allergy-induced inflammatory disease, such as asthma or multiple sclerosis. 5. The method according to claim 1, wherein said disease is rheumatoid arthritis. 6. The application of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating diseases mediated by tyrosine kinases, wherein the tyrosine kinases are BTK or SYK:

in R ¹ , R ² and R ⁴ independently represent R ⁸ -X-, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, hydrogen, halogen, nitro, cyano, -OH, -NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O) NH-OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _1-6 alkyl, -NHC(O)NH-OC _1-6 alkyl, -NHC(O) N(C _1-6 alkyl)-OC _1-6 alkyl, -S(O) ₂ NH-OC _1-6 alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _{1 -6} alkyl, or C _1-6 alkyl optionally substituted once or three times by halogen, hydroxy or alkoxy; R ³ is R ⁸ -X-, R ⁹ -X ¹ -, R ⁸ -X ¹ (CH ₂ ) _m -, R ⁹ -X ¹ (CH ₂ ) _m -, C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, hydrogen, halogen, nitro, cyano, -OH, -NH ₂ , -NH-C(O)H, -C(O)OH, -C(O)NH ₂ , -S(O) ₂ NH ₂ , -NHC(O)NH ₂ , -C(O)NH-OC _1-6 alkyl, -C(O)N(C _1-6 alkyl)-OC _{1- 6} Alkyl, -NHC(O)NH-OC _1-6 Alkyl, -NHC(O)N(C _1-6 Alkyl)-OC _1-6 Alkyl, -S(O) ₂ NH-OC _{1 -6} alkyl, -S(O) ₂ N(C _1-6 alkyl)-OC _1-6 alkyl, or C _1-6 alkyl optionally substituted one or three times by halogen, hydroxyl or alkoxy base; R ⁸ is C _3-7 cycloalkyl-T ¹ -, heterocyclyl-T ² -, aryl-T ³ -, heteroaryl-T ⁴ -, or optionally substituted one to five times by halogen C _1-6 alkyl; R ⁹ is C _1-6 alkyl, wherein said alkyl is substituted one to three times by: hydroxyl, alkoxy, amino, C _1-6 alkylamino, C _1-6 dialkylamino, C _{1-6 6} Alkylthio, C _1-6 Alkylsulfinyl, C _1-6 Alkylsulfonyl, C _1-6 Alkylsulfamoyl, C _1-6 Dialkylsulfamoyl, C _1-6 Alkane Sulfonylamino or heterocyclylsulfonyl; X is -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -N(C _1-6 alkyl)C(O)-, -NHC(O)-, - NHC(O)NH-, -NHC(O)N(C _1-6 alkyl)-, -OC(O)N(C _1-6 alkyl)-, -NHS(O) ₂ -, -S( O) ₂ NH-, -S(O) ₂ N(C _1-6 alkyl)-, -S(O) ₂ -, -S(O)-, -C(O)O-, -OC(O )-, -C(O)-, -NH-, -N(C _1-6 alkyl)-, -O- or -S-; X ¹ is -S(O) ₂ -, -S(O)-, -OC(O)-, -C(O)-, -NH-, -N(C _1-6 alkyl)-, -O -or-S-; T ¹ , T ² , T ³ and T ⁴ independently represent a single bond or an alkylene group optionally substituted once or twice by hydroxy; R ⁵ is hydrogen optionally substituted once or several times by halogen or alkoxy C _1-6 alkyl, heteroaryl, or phenyl optionally substituted once or twice by: halogen, -NO ₂ , -OH, -C(O)OH, - C(O)NH-aryl, -C(O)NH ₂ , -C(O)NH-C _1-6 alkyl, -C(O)N(C _1-6 alkyl) ₂ , -C( O)-heterocyclyl, -NH ₂ , -NHC(O)-aryl, -NHC(O)-C _3-7 cycloalkyl, -NHC(O)-C _1-6 alkyl, -N( C _1-6 alkyl) C (O) -C _1-6 alkyl, -NHC (O) OC _1-6 alkyl, -N (C _1-6 alkyl) C (O) OC _1-6 alkane Base, -NHC(O)-C _1-6 alkoxyalkyl, -NH-S(O) ₂ -aryl, -NH-S(O) ₂ -C _1-6 alkyl, -C(O )NH-S(O) ₂ -aryl, -C(O)NH-S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -alkyl, -NH-aryl, -O -aryl, -S(O)-aryl, aryl, heterocyclyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylthio , the alkyl, alkoxy and alkylthio groups are optionally substituted one or three times with: halogen; naphthyl optionally independently substituted with one to three halogens, benzene independently substituted with three halogens Base; 1,3-dihydro-isobenzofuryl, benzo[1,3]dioxol-5-yl, C _3-7 cycloalkyl or C _1-6 alkenyl; Y is an alkylene, alkylene-C(O)- or alkylene-CH(OH)-; m is 1-5; n is 0 or 1; R is ^hydrogen , C _1-6 alkyl, cyano or halogen; and R ⁷ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl. 7. The present invention as described above.